Abstract
Heterogeneous nuclear ribonucleoprotein A/B (hnRNPA/B) is one of the core members of the RNA binding protein (RBP) hnRNPs family, including four main subtypes, A0, A1, A2/B1 and A3, which share the similar structure and functions. With the advance in understanding the molecular biology of hnRNPA/B, it has been gradually revealed that hnRNPA/B plays a critical role in almost the entire steps of RNA life cycle and its aberrant expression and mutation have important effects on the occurrence and progression of various cancers. This review focuses on the clinical significance of hnRNPA/B in various cancers and systematically summarizes its biological function and molecular mechanisms.
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Facts
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Heterogeneous nuclear ribonucleoproteins (hnRNPs) are the most abundant nuclear protein in higher eukaryotes and a class of typical and acknowledged RNA binding proteins.
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HnRNPA/B subfamily is the core members of hnRNPs and closely associated with cancer initiation and progression.
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HnRNPA/B shows dynamic changes in human cancer progression and is identified as a promising biomarker of cancer.
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The regulatory network of hnRNPA/B in cancer is complex and diverse and has received widespread attention.
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Inhibitors targeting hnRNPA/B are continually being explored for clinical use, and a number of compounds of food, plant or traditional Chinese herbal are increasingly being found to contribute in cancer therapy by targeting hnRNPA/B.
Open Questions
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What are the specific mechanisms that cause the signature alterations of hnRNPA/B in cancer?
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Whether there are distinguished functions among hnRNPA/B members or even different isoforms?
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Why do members of the same hnRNPA/B subfamily appear to have contrasting expression and effects in the same cancer?
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Can hnRNPA/B achieve true clinical translation as a marker for cancer surveillance and a target for cancer treatment?
Introduction
Heterogeneous nuclear RNAs (hnRNAs) are the major transcripts of RNA polymerase II in eukaryotes. The nascent mature hnRNAs indiscriminately bind to numerous proteins to form complexes during transcription, and heterogeneous nuclear ribonucleoproteins (hnRNPs) are precisely the integral protein components of these complexes [1]. HnRNPs are the most abundant nuclear protein in higher eukaryotes and a class of typical and acknowledged RNA binding proteins (RBPs) [2]. About 20 major members (A-U) of the hnRNPs family were separated from eukaryotic cells [3]. Among them, hnRNPA1 and A2 alone have been identified to account for approximately 60% of the hnRNPs mass and are the important particles of hnRNPs’ biological roles in the life cycle [4].
The hnRNPA/B subfamily is the core member of hnRNPs, mainly including four isoforms hnRNPA0, A1, A2/B1, and A3 [5]. Recently, the biological value of hnRNPA/B has been widely discussed and highly valued. HnRNPA/B members share similar biogenesis and penetrate extensively and deeply into all levels of cellular RNA metabolism, participating in DNA binding, RNA splicing and trafficking, and mRNA translation and stability [6]. Although the structural characterization of hnRNPA/B and its role in RNA homeostasis have been studied and summarized in detail [7], the different biological functions of its four isoforms in human cancers are vital topics that cannot be overlooked. This review focuses on recent insights into the role and value of hnRNPA/B in cancer. This is the first comprehensive and systematic review of the differential expression, biological function, molecular mechanisms and clinical significance of hnRNPA/B in multiple cancers, providing a research summary and theoretical support for hnRNPA/B members as promising cancer biomarkers and therapeutic targets.
Profiles of hnRNPA/B: structure and intracellular localization
The ability of hnRNPA/B to co-package RNA into an array of regular ribonucleosomes is inextricably linked to its structural features [8]. HnRNPs consist of RNA-binding domains (RBDs) and auxiliary domains [9], which guiding hnRNPs to interact with target genes or other proteins by recognizing specific nucleotide sequences in the open reading frame (ORF) or untranslated region (UTR) [10]. Currently, RNA recognition motif (RRM), Arg-Gly-Gly (RGG) box and K-Homology (KH) motif are the main RBDs that have been authenticated maturely [11]. Among them, RRM is the most common and highly conserved sequence, shared by most hnRNPs family members [12]. While the number and spacing of RGG repeats vary considerably in different members [11]. And KH motif only presents in hnRNPE1, E2 and K [13]. As for the auxiliary domain, it is a dispersed and unstructured region that includes glycine-, alanine- or proline-rich domains [2, 9], perhaps influencing the RNA-binding site of hnRNPs to some extent [14]. In addition, the nuclear localization signal (NLS) and nucleo-cytoplasmic shuttling (NS) domains are also important components of hnRNPs, and their integrity is essential for mediating hnRNP nuclear imports [15].
To sum up, hnRNPA/B is a subgroup of proteins sharing similar structures consisting of two RRM and a glycine-rich domain that further encompasses an RGG box, an M9-NLS and a core prion-like domain (PrLD) [6, 16]. HnRNPA/B is predominantly localized in the eukaryotic nucleus and can accompany RNA transcripts into the cytoplasm in cooperation with the nuclear pore complex (NPC) [17]. It is reported that the GTPase Ran-GTP/GDP concentration gradient is crucial for maintaining the intracellular localization of hnRNPA/B [18]. Remarkably, hnRNPA/B is distinguished from a confusingly named protein, hnRNPAB (also known as CBF-A). Although they both share the characteristic RBD structural domain [19], the conserved amino acids that make up the primary structure differ from each other, so they are divided into two distinct subgroups, A and D [20]. Studies suggested that the completely different evolutionary directions between hnRNPA/B and hnRNPAB might lead to very different biological functions, but this review will not dwell on this but will focus only on the progress of hnRNPA/B family members in cancer.
HnRNPA/B possesses similar and distinct biological functions from other hnRNPs family members. Precisely, even individual members of the same hnRNPA/B subfamily exhibit diverse effects on the cancer microenvironment [21]. Consequently, distinguishing different hnRNPA/B members and understanding their specific biological functions in cancers will be of great significance.
The roles of hnRNPA/B in cancers: molecular mechanisms and clinical significance
HnRNPA0
HnRNPA0 is an important partner in RNA processing that can be phosphorylated by MAPKAP-K2 at Ser84 and induced by lipopolysaccharide (LPS) to assist in post-transcriptional regulation of specific mRNAs under inflammatory stimulation [22]. Recently, the abnormality of hnRNPA0 has gradually proved to be firmly associated with cancer development. Studies have shown that hnRNPA0 is located within the commonly deleted segment of 5q31.2 in myeloid neoplasms (MNs) with a del(5q). It is highly expressed in hematopoietic stem cells (HSCs) common-myeloid progenitors (CMPs) and megakaryocyte-erythrocyte progenitors (MEPs) and suppressed as cells differentiate towards different hematopoietic lineages. Meanwhile, a decreased dose of hnRNPA0 in therapy-related myeloid neoplasms (t-MNs) patients may contribute to leukemogenesis. Hence, haploinsufficiency of hnRNPA0 was considered as one of the key initiating mutations in the pathogenesis of MNs with a del(5q) [23]. Interestingly, hnRNPA0 mutation has also been found to be related to increased cancer incidence in a large family cursed with strong familial susceptibility to cancers [24].
Moreover, hnRNPA0 was also regarded as a strong promoter for various cancers such as hereditary colorectal cancer (CRC) [25], metastatic clear cell renal cell carcinoma (ccRCC) [26] and endometrial cancer (EC) [27]. It was reported that cancer-specific phosphorylated hnRNPA0 facilitated chromosomal alignment in mitosis and promoted CRC cell progression through RAB3GAP1-ZWINT1 cascade. The deactivation or deletion of the phosphorylated site of hnRNPA0 (Ser84) could weaken the interaction between hnRNPA0 and RAB3GAP1, thereby inducing proteasomal degradation of ZWINT-1 activated by Rab3 and CRC cell apoptosis [28]. In addition, hnRNPA0 was deemed as a “successor” to p53 for checkpoint control. Like p53, hnRNPA0 was activated by a checkpoint kinase (MK2) and simultaneously controlled cell cycle checkpoints. But unlike p53, hnRNPA0 repaired DNA damage caused by chemotherapy and drove cisplatin resistance by the post-transcriptional stabilization of p27(Kip1) and Gadd45α mRNAs [29, 30]. However, the translation process and oncogenic effects of hnRNPA0 could be hindered by lncRNA miR205HG in esophageal carcinoma (ESCA), in which hnRNPA0 was highly expressed [31].
Actually, the study on hnRNPA0 in cancer is still in its infancy (Fig. 1A), and its specific mechanisms and molecular regulatory networks in the cancer process remain unclear, thus there is still a long way to go to reach the final clinical transformation.
HnRNP A1
HnRNPA1 is one of the most abundant and ubiquitously expressed nuclear proteins. HnRNPA1-a (a short variant) and A1-b (a full-length variant) are the main variants that have been experimentally verified [4]. HnRNPA1 is the most well studied member of hnRNPA/B and plays a key role in a variety of cancers(Fig. 2). The ectopic expression of hnRNPA1 at different disease stages or sites has been progressively proved to be correlated with pathophysiological features and clinical prognosis of cancers, indicating hnRNPA1 as a promising cancer biomarker. Given its significance in cancer, hnRNPA1 has also been employed as a drug target in clinical trials, which may bring a new opportunity for cancer prevention and treatment in the near future.
Expression, function and significance of hnRNPA1 as an oncogene in diverse cancers
As report goes, hnRNPA1 was the most frequently (76%) overexpressed hnRNPA/B family protein in non-small cell lung cancer (NSCLC) [32] and was negatively correlated with the overall survival of patients with lung cancer [33]. HnRNPA1 could augment the proliferation activity of lung cancer cells by directly binding to the 3ʹUTR of vaccinia related kinase 1 (VRK1) mRNA, expediting its translation and then increasing cyclin D1 expression [33]. Similarly, hnRNPA1 has also been found to be highly expressed in sentinel lymph nodes, tissues and serum of CRC patients [34, 35]. In promoting CRC course, hnRNPA1 could link to 3ʹUTR of autophagy-related gene 6 (ATG6) mRNA and mediate G4 formation of TRA2B [36]. These findings implied that hnRNPA1 may become a potential cancer biomarker and therapeutic target.
Furthermore, hnRNPA1 was reported to be bound and phosphorylated on novel Ser4/6 sites by fibroblast growth factor 2 (FGF-2)-induced S6 kinase 2 (S6K2) [37]. Meanwhile, the RNA binding activity of hnRNPA1 could be interfered with by protein arginine methyltransferase 3 (PRMT3) via methylation modification [38]. Moreover, the localization of hnRNPA1 and its impact on mRNA alternative splicing could be affected by establishment of cohesion 1 homolog 2 (ESCO2)-mediated acetylation [39] and SPRY domain-containing SOCS box protein 1 (SPSB1)-induced ubiquitylation [40].
Therefore, based on existing research, hnRNPA1 was identified as a novel cancer indicator. With the upstream mechanisms of hnRNPA1 being unveiled gradually, it is initially clear that multiple post-translational modifications are important factors affecting the stability and molecular function of hnRNPA1.
The molecular mechanisms of hnRNPA1 involved in modulating cancer progression
Mechanically, hnRNPA1, a classical RBP, is involved in regulating the splicing and maturation of various key cancer genes, in which hnRNPA1 arginine methylation was found to play a prominent role [41]. In breast cancer (BC), hnRNPA1 affect the malignant properties of cancer cells by mediating the CEACAM1-S/-L ratio [42]. Likewise, the ratio of CCDC50-FL and CCDC50-S was also adjusted by hnRNPA1 in ccRCC, which could accelerate ccRCC progression through promoting the carcinogenic transformation of CCDC50-S [43]. Moreover, hnRNPA1 could interact with HPV18 exonic splicing silencer (ESS) [44] and HPV16 late regulatory element (LRE) [45], respectively, participating in balancing the splicing of HPV18 and HPV16 pre-mRNAs [46]. These ultimately catalyzed the malignant transformation of HPV and provided another potential target for HPV-related cancers. Additionally, the spliced variants of cyclin-dependent kinases 2 (CDK2) and transmembrane receptor for hyaluronic acid CD44 were both manipulated by hnRNPA1 to drive the development of oral squamous cell carcinoma (OSCC) and metastatic BC [47, 48].
It is worth noting that hnRNPA1 has been shown to alter aerobic glycolysis of cancer cells by directing the alternative splicing of pyruvate kinase (PKM) [49]. Concretely, the combination between the RGG motif of hnRNPA1 and the sequences flanking PKM exon 9 was enhanced by STAT3, thereby inhibiting PKM1 isoform formation and inducing PKM2 isoform production. However, this process was in turn blocked by microRNA let-7a-5p, thus forming a feedback loop between let-7a-5p, STAT3 and hnRNPA1 as a new way mediating aerobic glycolysis of BC [50]. As in other cancers, hnRNPA1-mediated variable splicing of PKM was essential for accelerating cellular glycolysis, and upstream promoters such as lncRNA SNHG6 and ESCO2, and repressors such as RBMX and miR-206 may affect the smooth advancement of this process by interacting with hnRNPA1 [39, 50,51,52].
Certainly, hnRNPA1 was also a critical mediator for multiple cancer regulators. For instance, hnRNPA1 could recognize the specific DNA conformation of KRAS, a G4 structure, and form an EGF-KRAS-ILK-hnRNPA1 regulatory loop to maintain the invasive activity of pancreatic ductal adenocarcinoma (PDAC) cells [53, 54]. Additionally, hnRNPA1 was involved in tumor immune responses as well. Ectopic hnRNPA1 elicited thapsigargin-induced endoplasmic reticulum (ER) stress, promoted translation of specific melanoma-overexpressed antigen 1 (MELOE-1), and further enhanced recognition of melanoma cells by MELOE-1-specific T-cell clone, improving their immune efficacy [55]. Moreover, hnRNPA1 played an important role in mediating hormone homeostasis. HnRNPA1 was found to selectively suppress androgen receptor (AR) transactivation via interruption of AR-ARA54 interaction and ARA54 homodimerization in prostate cancer (PCa) [56]. HnRNPA1 was also intimately involved in promoting intercellular communication between mesenchymal cancer cells and blood vessel endothelium. Detailedly, hnRNPA1 encapsulated miR-27b-3p into exosomes and delivered them into vascular endothelial cells, setting the stage for subsequent exosomal miR-27b-3p promotion of circulating tumor cell-mediated cancer cell metastasis [57]. Coincidentally, the effect of hnRNPA1 in assisting the packaging of different molecules into extracellular vesicles (EVs) was successively discovered. Currently, it was well documented that hnRNPA1 could be recruited by USP7 to facilitate exo-lncFERO and exo-miR-522 secretion, aiding their regulating of lipid metabolism, ferroptosis and individual chemosensitivity gastric cancer (GC) cells [58, 59]. Analogously, the role of hnRNPA1 loading batched miRNAs/lncRNAs into EVs was revealed in lung cancer, bladder cancer (BCa) and advanced head and neck cancer (HNC) as well [60,61,62]. More than that, hnRNPA1 was demonstrated to be concerned in mediating PCa enzalutamide (Enz) sensitivity via lnc-OPHN1-5/AR interaction [63], promoting triple-negative breast cancer (TNBC) progression via competitively binding to lncRNA HYOU1-AS [64], sustaining activation of NF-κB pathway in PDAC via lncRNA-PLACT1/IκBα/E2F1 feedback loop [65], and regulating ovarian cancer (OC) chemoresistance via miR-18a-KRAS axis [66].
Collectively, the molecular mechanisms of hnRNPA1 in cancer development are complicated, whether it is involved in pre-mRNA splicing and processing, competitively binding to varied RNAs, or assisting in EVs packaging and secretion. As the research on hnRNPA1 moves along, its application in cancers will attract more and more attention.
Advances in drugs targeting hnRNPA1
In recognition of the importance of hnRNPA1, numerous hnRNPA1-targeting compounds have been developed successively for clinical treatment of cancers (Fig. 3). VPC-80051, the first small molecule inhibitor targeting hnRNPA1 RBD to be synthesized, could dramatically reduce androgen receptor AR-V7 messenger levels in castration-resistant prostate cancer (CRPC) cell lines and significantly improve the therapeutic effect of PCa [67]. Presently, many existing drugs, foods and plant ingredients have been unearthed in succession for cancer treatment by targeting hnRNPA1. In PCa, hnRNPA1 was identified as a direct anti-cancer target of quercetin, a flavonoid abundantly present in plants. Binding to the C-terminal region of hnRNPA1, quercetin hindered hnRNPA1’s combination with transportin 1 (Tnpo1), leading to its cytoplasmic retention and subsequent recruitment of hnRNPA1 to stress granules (SGs), ultimately putting cancer cells on the path to apoptosis [68]. Meanwhile, esculetin, a coumarin derivative from several herbs, was shown to induce apoptosis of endometrial cancer cells by affecting the nucleocytoplasmic transport of the hnRNPA1-BCLXL/XIAP mRNA complex [69]. Additionally, hnRNPA1-specific single-stranded DNA aptamer, BC15, was developed as a potential drug candidate for hepatocarcinoma treatment [70]. Of interest, tetracaine, a local anesthetic with potent anticancer effects, was reported to cause melanoma cell cycle arrest by driving hnRNPA1 accumulation at the nuclear envelope and weakening hnRNPA1 protein stability [71], providing new evidence for the potential benefits of applying local anesthetics in cancer patients.
With the deepening of clinical and basic research on hnRNPA1, its important role in cancer origination and progression continues to emerge. HnRNPA1 is a biomarker with considerable clinical transformation value, whether for cancer early screening or targeted therapy.
HnRNPA2/B1
HnRNPA2/B1 and A1 are the two most studied members of the hnRNPA/B family. HnRNPA2/B1 gene generates four splice variants, namely A2, A2b, B1 and B1b [72]. Although there is only a 12 amino acid difference between hnRNPA2 and B1, their expression is not identical throughout the cell cycle, in different tissue types, and at different disease stages. It has been established that hnRNPA2 and B1 may have distinct functions due to their slightly different preferences for RNA sequences [73]. However, although some findings have highlighted the importance of considering the specific functions of hnRNPA2/B1 spliceoforms, most studies have not distinguished between these isoforms yet [74].
HnRNPA2/B1 is recommended as a promising cancer biomarker
In manifold cancers, hnRNPA2/B1 has been shown to exhibit high expression level and to be strongly associated with clinic-pathological features and prognosis. During mammalian lung development, hnRNPA2/B1 presents a dynamic process, with increased level closely correlating to lung precancerous lesion and lung cancer progression [75, 76]. Meanwhile, the sensitivity of hnRNPA2/B1 in NSCLC was 84.8% in brushing and 80.8% in biopsies, while 66.7% and 75% in small cell lung cancer (SCLC), respectively [77]. Supported by extensive research data, hnRNPA2/B1 was considered an independent risk factor for lung cancer and could be applied for early assessment, disease surveillance and prognosis prediction of lung cancer [78, 79]. Analogously, hnRNPA2/B1 has been found to be elevated in both hepatitis virus-positive liver tissues and hepatocellular carcinoma (HCC) tissues. Interestingly, the localization of hnRNPA2/B1 was altered during the transition from hepatitis virus infection to poorly differentiated HCC, suggesting that hnRNPA2/B1 could be employed for assessing HCC risk [80]. Also, abnormal hnRNPA2/B1 was thought to serve as an oncogenic driver of glioblastoma and was correlated with poor prognosis [81]. HnRNPA2/B1 co-localization with c-myc, c-fos, p53, and Rb was translocated to the cytoplasm, through which hnRNPA2/B1 played a key role in the differentiation of GC cells [82].
In conclusion, growing numbers of basic and clinical data elucidate the potential and value of hnRNPA2/B1 as a biomarker of cancers, particularly lung cancer and HCC, emphasizing the feasibility of achieving the application of hnRNPA2/B1 in clinical practice.
Molecular mechanisms of hnRNPA2/B1 as a cancer driver gene
Throughout previous studies, it is easy to find that hnRNPA2/B1 typically acts as a cancer driver gene and influences the biological behaviors of cancer cells mainly by modulating PI3K/Akt, Wnt/β-catenin, MAPK/ERK and other signaling cascades. For instance, in PDAC, cervical cancer and multiple myeloma (MM), hnRNPA2/B1 could promote cancer cell growth and metastasis and impair their sensitivity to gemcitabine, 5-fluorouracil (5-FU), oxaliplatin, lobaplatin and irinotecan by activating KRAS-PI3K interaction or regulating ILF3-mediated Akt signals [83,84,85,86]. HnRNPA2/B1 also could expedite cancer progression by controlling the ERK/snail, p53/HDM2 and Wnt/β-catenin signaling [87,88,89]. Moreover, the targets of hnRNPA2/B1 are rich and diverse. HnRNPA2/B1 could serve as a trigger for RNA switch to modulate the function of miRNAs or lncRNAs in cancer cells [90]. Illustratively, hnRNPA2/B1 affected the prognosis of ESCA by regulating the miR-17-92 cluster [91], facilitated the malignant phenotype of OC by activating Lin28B [92], and advanced lung cancer progression by contributing to miR-106b-5p maturation [88]. In some cases, the oncogenic roles and expression of hnRNPA2/B1 were instead impacted by certain upstream effectors. In triggering NSCLC growth, hnRNPA2/B1 could be acetylated by transcriptional co-activator p300 [93]. And in the process of hnRNPA2/B1 promoting VHLα translation in renal cancer, the hnRNPA2/B1 level was in turn repressed by elevated VHLα [94].
Absolutely, the initial role of hnRNPA2/B1 in alternative splicing is not negligible. HnRNPA2/B1 could specifically recognize the AUGGUA motif upstream of HPV-16 5ʹ-splice site SD3632 and inhibited HPV-16 L1 production, enabling HPV-16 to evade the immune system and establish long-term persistent infection [95]. Moreover, hnRNPA2/B1 could exclude cassette exon 11 from macrophage stimulating 1 receptor (MST1R) and resulted in the generation of recepteur d’origine nantais ∆165 (RON∆165) isoform [96]. Similarly, the exon selective splicing in the 5ʹUTR of TP53INP2 was a key event downstream of hnRNPA2 [97]. In addition, the oncogenic isoform 202 of the anti-apoptotic factor BIRC5 was also managed by hnRNPA2/B1 [98].
The two isoforms of hnRNPA2/B1, A2 and B1, were distinguished for exploration in some experiments. In an inflammation-induced mouse model, upregulated hnRNPA2 induced immortalized liver progenitor cell formation. This finding pointed out that it was hnRNPA1, but not B1, that reduced the dominant-negative isoform of A-Raf and led to activation of Raf-MEK-ERK pathway in GC [99]. Furthermore, the low level of hnRNPA2 was captured in paclitaxel-resistant OC cells and was considered to be an important hallmark of OC chemoresistance, in which the possible contribution of hnRNPB1 was not discussed [100].
However, hnRNPA2/B1 may even exert seemingly contradictory biological effects in the same cancer, particularly in BC. Most studies have shown that hnRNPA2/B1 was increased in BC [101], negatively correlated with cancer suppressor breast cancer susceptibility gene 1 (BRCA1) [102], and was a marker of poor prognosis in patients with BC [103]. Serving as a cancer promoter, hnRNPA2/B1 could force the autophagy, growth and endocrine resistance of BC cells [104,105,106]. In contrast, hnRNPA2/B1 was reported to be decreased in the Breast Cancer Integrative Platform and to have a dramatically inhibitory effect on the distant metastasis of TNBC [107]. Mechanically, hnRNPA2/B1 bound to BC cell metastasis booster profilin 2 (PFN2) directly and reduced its stability. Silencing hnRNPA2/B1 activated ERK-MAPK/Twist and GR-beta/TCF4 pathways, but inhibited STAT3 and WNT/TCF4 signaling pathways [107]. Therefore, the molecular mechanisms of hnRNPA2/B1 in BC are variable, and the final effect it produces may be the result of a dynamic balance, which demands more exploration.
Conclusively, hnRNPA2/B1 is an extremely prospective cancer driver. Its biological functions in cancers, especially in BC, are not unidirectional or unique. More systematic and in-depth studies are required in the future to provide more detailed theoretical support.
The mechanisms of hnRNPA2/B1 as a “cooperator” in cancer progression
A wealth of data have indicated that hnRNPA2/B1 is involved in various cancer networks as a “cooperator”. In other words, hnRNPA2/B1 is a dominant mediator of diverse cancer driver genes. Such as, hnRNPA2/B1 was recruited by Nm23-H1 to co-regulate Sp1 translation and thus increased lung cancer cell malignant degree [108]. HnRNPA2/B1 was utilized by the ubiquitin-like protein interferon-stimulated gene 15 (ISG15) to enhance OC cell responses to cisplatin [109]. The antioxidant uncoupling protein 2 (UCP2) sustained the metabolic shift from mitochondrial oxidative phosphorylation (mtOXPHOS) to glycolysis in pancreatic cancer (PC) cells with the help of hnRNPA2/B1 [110], through which the Src family kinase Fyn could modulate PC cell apoptosis as well [111]. In addition, the formation of the MIR100HG/hnRNPA2B1/TCF7L2 forward-regulatory loop and the c-MYC/LINC01234/hnRNPA2B1/miR-106b-5p/Cry2/c-MYc positive-feedback loop could effectively accelerate disease progression in cancer patients [112]. In terms of cooperation with different types of RNAs, hnRNPA2/B1 could interact with Linc01232 [113], lncRNA H19 [114] and circMYH9 [115], and bolster their work in cancer evolvement. Interestingly, under the specific mediation of hnRNPA2/B1, H19 was observed could be wrapped into exosomes and promote gefitinib resistance in lung cancer [116].
HnRNPA2/B1 is a core component of animated RNA packaging and a key modulator of vesicular RNA sorting [117]. In addition to H19 described above, lncRNA LNMAT2 could also be loaded by hnRNPA2/B1 into BCa-secreted exosomes to expedite lymphangiogenesis and lymphatic metastasis [118]. Surely, not only on lncRNAs, but also hnRNPA2/B1 could act on miR-122-5p EXO-motif to induce hepatic metastasis of lung cancer [119], and similarly could motivate exo-miR-394-mediated M2 polarization of macrophages [120]. Moreover, tumor-derived EVs-miR-378a-3p was enriched by hnRNPA2/B1 overexpression as well [121].
The results above well illustrated the importance of hnRNPA2/B1 in the microscopic world of cancer molecular regulation. HnRNPA2/B1 is required in multiple aspects of cancer growth and development, the list goes on and on (Fig. 4).
Therapeutic exploration targeting hnRNPA2/B1
Considering the high impact of hnRNPA2/B1 on cancers, clinical attempts to target hnRNPA2/B1 are ongoing (Fig. 5). Cotyledon orbiculata, an extract of a South African medicinal plant, was revealed to induce apoptosis of CRC and ESCA cells by propelling hnRNPA2/B1 splicing from B1 to A2 [122]. Moreover, apigenin and other dietary flavones are emerging as potential chemo-sensitizers and have also been found to cause TNBC cell apoptosis by binding to hnRNPA2/B1 [123]. Specifically, hnRNPA2 deletion partially attenuated apigenin-induced sensitization of TNBC spheroids to doxorubicin through declining the efflux transporter ABCC4 and ABCG2. These findings provided a new perspective on the clinical value of hnRNPA2/B1 and underscored the rationality of using dietary compounds as chemotherapeutic adjuvants. In the course of investigating therapeutic strategies targeting hnRNPA2/B1, Li et al. [124]. identified that C6-8, an aptamer targeting ROS17/2.8 cells, could specifically bind to hnRNPA2/B1 and precisely label multiple cancer cell lines with fluorescent carbon nanodots (CDots) conjugation. In addition, hnRNPA2/B1 has also been discovered as a direct target candidate for tamoxifen analog Ridaifen-G (RID-G) in its potent anticancer working [125].
In general, hnRNPA2/B1 has shown the potential druggability for application as an excellent therapeutic target, meriting further investigations.
HnRNP A3
HnRNPA3 is a relatively less studied member of the hnRNPA/B family and two isoforms, hnRNPA3a and 3b, have been reported, with hnRNPA3a being the only isoform detected in human cells [126]. HnRNPA3, with roughly the same structural features as other hnRNPA/B members, could bind to cis-acting response elements within mRNA 3ʹUTR and was important in the stable maintenance of telomere repeats and RNAs life cycle [127, 128]. For example, hnRNPA3 could recognize nuclear RNA export factor 7 (NXF7) in differentiated neuroblastoma cells and form a stable complex, taking part in the sorting, transport and/or storage of mRNAs [129].
Continuous research of hnRNPA3 has led to a growing understanding of its functions. In addition to its effects on cell senescence [130], differentiation [131] and neurodegeneration [132], hnRNPA3 is of great interest for its value in cancer (Fig. 1B). HnRNPA3 was found to increase gradually in the progression from cirrhosis, dysplastic nodules (DNs) and well-differentiated HCC to progressed HCC, and its expression level could be used to differentiate between high-grade dysplastic nodule (HGDN) and early HCC (eHCC), particularly in combination with glypican 3 (GPC3), with a specificity of 100%. Meanwhile, upregulated hnRNPA3 has been verified to strongly associate with poor survival of patients with HCC. Therefore, hnRNPA3 was proposed as a valuable differential diagnostic and prognostic biomarker during the multistep process of HCC carcinogenesis [133]. Furthermore, hnRNPA3 exhibited potential as a marker for advanced CRC in proteomics [134] and showed a high correlation with lymph node metastasis and poor prognosis in BCa patients undergoing radical cystectomy in a retrospective clinical study [135]. Simultaneously, hnRNPA3 was a key candidate protein related to BCa cisplatin resistance [136] and glioblastoma TMZ resistance [137], and was even a crucial regulator improving the efficacy of irinotecan enhanced by the traditional Chinese herbal preparation PHY906 [138]. These suggested that hnRNPA3 might have significant utility in clinical efficacy predicating. However, compared with that of other family members, the response of hnRNPA3 in lung cancer cell lines under acidosis, hypoxia, and serum deprivation conditions was the lowest and most constant [21], indicating that hnRNPA3 might be less sensitive in reflecting the survival status of cancer cells under stressful conditions.
Additionally, hnRNPA3 could significantly affect the subcellular localization of the classical oncogene EGFR. HnRNPA3 depletion reduced the nuclear accumulation of EGFR, accompanied by attenuated NSCLC growth vitality [139]. Also, hnRNPA3 was one of the downstream responders of miR-200b, a powerful regulator of the epithelial-mesenchymal transformation (EMT) in NSCLC [140]. Moreover, hnRNPA3 could also assist in the substantial elevation of APOBEC3B (A3B) in multiple cancers, which was a driver for the induction of unexpected mutation clusters [141].
In brief, research on hnRNPAs3 is still not in-depth, while hnRNPA3 shows great value in scientific studies and clinical applications. More efforts should be spent henceforth to comprehensively understand the specific function and molecular mechanisms of hnRNPA3.
Interaction between members of the hnRNPA/B family
Although hnRNPA/B plays a key role in cancer progression, much remains to be discovered on how hnRNPA/B members interact with each other. Previously, some studies attempted to elucidate the interaction of hnRNPA/B. Among them, a protein interaction reporter (PIR)-based crosslinker was applied and thus hnRNPA1 and A2/B1 were shown to have a high level of amino acid sequence identity and both could crosslink with lysine residues K42 of hnRNPC [142]. Moreover, the Gly-rich domains of the two proteins were identified to bind to the trans-activation response DNA-binding protein 43 (TDP-43) [143] and H1-84mAb of influenza virus hemagglutinin [144], causing nervous system damage. According to the current researches, hnRNPA1 and A2/B1 were verified to co-localize with TDP-43 in the cytoplasm of atrophic muscle fibers [143], as well as with C9ORF72 [145], DNAJB6 [146] and SMN1 [147], respectively, in stress granules. Furthermore, hnRNPA1 and A2/B1 were frequently present in the same complex and cooperated in molecular biological functions, such as regulating the transcription of cancer suppressor ANXA7 [148], controlling the splicing response to oxaliplatin-mediated DNA damage [149], acting as inhibitors of HPV16 E7 expression [46], accelerating the transcriptional elongation of P-TEFb-dependent genes [150], participating in the reversal of 5-Fu resistance in cancer cells [151], and modulating alternative splicing of PKM2 in proliferating cells [152]. In addition, hnRNPA/B members A2/B1 and A3 were also found to be contained in the same complex [153] and involved in maintaining embryonic and adult cell stemness by interacting with SOX2 [154].
Notably, hnRNPA1 and A2/B1 were reported to regulate each other’s expression in a compensatory manner at both RNA and protein levels and were confirmed to be mediated by their respective 3ʹUTRs [155]. Moreover, there was a complementary relationship between hnRNPA1 and A2/B1. When hnRNPA1 was deficient, A2/B1 could compensate for the A1 deficiency to aid distal 5ʹ splice site selection [156].
Studies above have provided some evidence for synergistic interactions of hnRNPA/B family members. However, to the best of our knowledge, the specific underlying mechanisms of interaction between members of the hnRNPA/B family are still not explored, which may become a focus for future hnRNPA/B family-related studies.
Summary and outlook
The paper presents a review on the relationship between the hnRNPA/B family and cancer occurrence and development, mainly focusing on the characteristic alterations and clinical significance of hnRNPA0, A1, A2/B1 and A3 in various cancers (Table 1) and comprehensively summarizing their biological functions and related molecular mechanisms involved (Table 2). HnRNPA/B can not only regulate the splicing, transcription, translation and translocation of targets but also coordinate or antagonize the roles of relevant functional genes in the malignant process of cancer.
Generally, hnRNPA/B exhibits a dynamic shift in human tissues. HnRNPA2/B1 was displaced and progressively elevated during the progression from precancerous lesions to advanced cancer stages, demonstrating its potential for dynamic cancer surveillance. Furthermore, hnRNPA3 combined with GPC3 can effectively differentiate between HGDN and eHCC, implying the aptitude of hnRNPA3 to differentially diagnose cancer. Whether other hnRNPA/B family members also present dynamic signature changes in other cancer progression remains to be further investigated.
HnRNPA/B is highly expressed in most cancers and is often predictive of disappointing survival and poor treatment outcomes. However, there are some contradictions. For instance, hnRNPA2/B1, generally upregulated in breast cancer, has been detected to be reduced in TNBC and negatively correlated with metastasis. Therefore, further distinguishing different pathological types, disease stages or treatment phases of cancer in future studies is necessary.
Furthermore, it is of fundamental significance to clarify the complex molecular mechanisms of hnRNPA/B. Firstly, in terms of the upstream mediums, the post-translational modifications cannot be ignored [157]. The level of hnRNPA/B can be manipulated as a result of ubiquitination, acetylation or phosphorylation. However, the available data are far from sufficient to explain the specific upstream mechanisms that shape hnRNPA/B in cancer. Secondly, hnRNPA/B participates in the entire process from RNA production to stabilization, and the molecular mechanisms involved are being discovered, but systematic and comprehensive research and summaries are not yet sufficient and more efforts are needed. In addition, the unknown network of interactions and mechanisms between members of the hnRNPA/B family is a novel topic worthy of further exploration in the future.
Having unraveling the potential of hnRNPA/B for clinical application, some investigators are beginning to devote themselves to exploring its targeted inhibitors or drugs. These include VPC-80051, BC15, quercetin, esculetin, kaempferol and tetracaine targeting hnRNPA1, and cotyledon orbiculata, C6-8, RID-G, apigenin and other dietary flavones targeting hnRNPA2/B1. These advances provide a starting point for conducting translational studies on hnRNPA/B.
In summary, breakthroughs in the comprehension of the role and mechanisms of hnRNPA/B in cancer malignant progression have yielded exceptional results in recent years. A large body of evidence suggests that hnRNPA/B, especially hnRNPA1 and A2/B1, have a good clinical value as a marker for early cancer diagnosis, disease monitoring, prognosis assessment and efficacy evaluation. It is very worthwhile to further explore hnRNPA/B, which will provide a new perspective for future individualized targeted cancer therapy, retaining very promising targets.
Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
References
Dreyfuss G, Matunis MJ, Pinol-Roma S, Burd CG. hnRNP proteins and the biogenesis of mRNA. Annu Rev Biochem. 1993;62:289–321.
Geuens T, Bouhy D, Timmerman V. The hnRNP family: insights into their role in health and disease. Hum Genet. 2016;135:851–67.
Pinol-Roma S, Choi YD, Matunis MJ, Dreyfuss G. Immunopurification of heterogeneous nuclear ribonucleoprotein particles reveals an assortment of RNA-binding proteins. Genes Dev. 1988;2:215–27.
Jean-Philippe J, Paz S, Caputi M. hnRNP A1: the Swiss army knife of gene expression. Int J Mol Sci. 2013;14:18999–9024.
Dangli A, Plomaritoglou A, Boutou E, Vassiliadou N, Moutsopoulos HM, Guialis A. Recognition of subsets of the mammalian A/B-type core heterogeneous nuclear ribonucleoprotein polypeptides by novel autoantibodies. Biochem J. 1996;320:761–7.
Thibault PA, Ganesan A, Kalyaanamoorthy S, Clarke JWE, Salapa HE, Levin MC. hnRNP A/B Proteins: an encyclopedic assessment of their roles in homeostasis and disease. Biology. 2021;10:712.
Mayeda A, Munroe SH, Caceres JF, Krainer AR. Function of conserved domains of hnRNP A1 and other hnRNP A/B proteins. EMBO J. 1994;13:5483–95.
Huang M, Rech JE, Northington SJ, Flicker PF, Mayeda A, Krainer AR, et al. The C-protein tetramer binds 230 to 240 nucleotides of pre-mRNA and nucleates the assembly of 40S heterogeneous nuclear ribonucleoprotein particles. Mol Cell Biol. 1994;14:518–33.
Krecic AM, Swanson MS. hnRNP complexes: composition, structure, and function. Curr Opin Cell Biol. 1999;11:363–71.
Xie W, Zhu H, Zhao M, Wang L, Li S, Zhao C, et al. Crucial roles of different RNA-binding hnRNP proteins in Stem Cells. Int J Biol Sci. 2021;17:807–17.
Kiledjian M, Dreyfuss G. Primary structure and binding activity of the hnRNP U protein: binding RNA through RGG box. EMBO J. 1992;11:2655–64.
Dreyfuss G, Philipson L, Mattaj IW. Ribonucleoprotein particles in cellular processes. J Cell Biol. 1988;106:1419–25.
Biamonti G, Riva S. New insights into the auxiliary domains of eukaryotic RNA binding proteins. FEBS Lett. 1994;340:1–8.
Weighardt F, Biamonti G, Riva S. The roles of heterogeneous nuclear ribonucleoproteins (hnRNP) in RNA metabolism. Bioessays. 1996;18:747–56.
Low YH, Asi Y, Foti SC, Lashley T. Heterogeneous nuclear ribonucleoproteins: implications in neurological diseases. Mol Neurobiol. 2021;58:631–46.
Liu Y, Shi SL. The roles of hnRNP A2/B1 in RNA biology and disease. Wiley Interdiscip Rev RNA. 2021;12:e1612.
Pinol-Roma S, Dreyfuss G. Shuttling of pre-mRNA binding proteins between nucleus and cytoplasm. Nature. 1992;355:730–2.
Reed R, Hurt E. A conserved mRNA export machinery coupled to pre-mRNA splicing. Cell. 2002;108:523–31.
Xu RM, Jokhan L, Cheng X, Mayeda A, Krainer AR. Crystal structure of human UP1, the domain of hnRNP A1 that contains two RNA-recognition motifs. Structure. 1997;5:559–70.
Akindahunsi AA, Bandiera A, Manzini G. Vertebrate 2xRBD hnRNP proteins: a comparative analysis of genome, mRNA and protein sequences. Comput Biol Chem. 2005;29:13–23.
Romero-Garcia S, Prado-Garcia H, Lopez-Gonzalez JS. Transcriptional analysis of hnRNPA0, A1, A2, B1, and A3 in lung cancer cell lines in response to acidosis, hypoxia, and serum deprivation conditions. Exp Lung Res. 2014;40:12–21.
Rousseau S, Morrice N, Peggie M, Campbell DG, Gaestel M, Cohen P. Inhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by MAPKAP-K2 and its interaction with cytokine mRNAs. EMBO J. 2002;21:6505–14.
Young DJ, Stoddart A, Nakitandwe J, Chen SC, Qian Z, Downing JR, et al. Knockdown of Hnrnpa0, a del(5q) gene, alters myeloid cell fate in murine cells through regulation of AU-rich transcripts. Haematologica. 2014;99:1032–40.
Wei C, Peng B, Han Y, Chen WV, Rother J, Tomlinson GE, et al. Mutations of HNRNPA0 and WIF1 predispose members of a large family to multiple cancers. Fam Cancer. 2015;14:297–306.
Belhadj S, Terradas M, Munoz-Torres PM, Aiza G, Navarro M, Capella G, et al. Candidate genes for hereditary colorectal cancer: Mutational screening and systematic review. Hum Mutat. 2020;41:1563–76.
Qian S, Sun S, Zhang L, Tian S, Xu K, Zhang G, et al. Integrative analysis of DNA methylation identified 12 signature genes specific to metastatic ccRCC. Front Oncol. 2020;10:556018.
Witek L, Janikowski T, Bodzek P, Olejek A, Mazurek U. Expression of tumor suppressor genes related to the cell cycle in endometrial cancer patients. Adv Med Sci. 2016;61:317–24.
Konishi H, Fujiya M, Kashima S, Sakatani A, Dokoshi T, Ando K, et al. A tumor-specific modulation of heterogeneous ribonucleoprotein A0 promotes excessive mitosis and growth in colorectal cancer cells. Cell Death Dis. 2020;11:245.
Cannell IG, Merrick KA, Morandell S, Zhu CQ, Braun CJ, Grant RA, et al. A pleiotropic RNA-binding protein controls distinct cell cycle checkpoints to drive resistance of p53-defective tumors to chemotherapy. Cancer Cell. 2015;28:623–37.
Reinhardt HC, Hasskamp P, Schmedding I, Morandell S, van Vugt MA, Wang X, et al. DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization. Mol Cell. 2010;40:34–49.
Dong X, Chen X, Lu D, Diao D, Liu X, Mai S, et al. LncRNA miR205HG hinders HNRNPA0 translation: anti-oncogenic effects in esophageal carcinoma. Mol Oncol. 2022;16:795–812.
Boukakis G, Patrinou-Georgoula M, Lekarakou M, Valavanis C, Guialis A. Deregulated expression of hnRNP A/B proteins in human non-small cell lung cancer: parallel assessment of protein and mRNA levels in paired tumour/non-tumour tissues. BMC Cancer. 2010;10:434.
Ryu HG, Jung Y, Lee N, Seo JY, Kim SW, Lee KH, et al. HNRNP A1 promotes lung cancer cell proliferation by modulating VRK1 translation. Int J Mol Sci. 2021;22:5506.
He ZY, Wen H, Shi CB, Wang J. Up-regulation of hnRNP A1, Ezrin, tubulin beta-2C and Annexin A1 in sentinel lymph nodes of colorectal cancer. World J Gastroenterol. 2010;16:4670–6.
Ma YL, Peng JY, Zhang P, Huang L, Liu WJ, Shen TY, et al. Heterogeneous nuclear ribonucleoprotein A1 is identified as a potential biomarker for colorectal cancer based on differential proteomics technology. J Proteome Res. 2009;8:4525–35.
Nishikawa T, Kuwano Y, Takahara Y, Nishida K, Rokutan K. HnRNPA1 interacts with G-quadruplex in the TRA2B promoter and stimulates its transcription in human colon cancer cells. Sci Rep. 2019;9:10276.
Roy R, Durie D, Li H, Liu BQ, Skehel JM, Mauri F, et al. hnRNPA1 couples nuclear export and translation of specific mRNAs downstream of FGF-2/S6K2 signalling. Nucleic Acids Res. 2014;42:12483–97.
Hsu MC, Pan MR, Chu PY, Tsai YL, Tsai CH, Shan YS, et al. Protein arginine methyltransferase 3 enhances chemoresistance in pancreatic cancer by methylating hnRNPA1 to increase ABCG2 expression. Cancers (Basel). 2018;11:8.
Zhu HE, Li T, Shi S, Chen DX, Chen W, Chen H. ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation. J Exp Clin Cancer Res. 2021;40:64.
Wang F, Fu X, Chen P, Wu P, Fan X, Li N, et al. SPSB1-mediated HnRNP A1 ubiquitylation regulates alternative splicing and cell migration in EGF signaling. Cell Res. 2017;27:540–58.
Li WJ, He YH, Yang JJ, Hu GS, Lin YA, Ran T, et al. Profiling PRMT methylome reveals roles of hnRNPA1 arginine methylation in RNA splicing and cell growth. Nat Commun. 2021;12:1946.
Dery KJ, Gaur S, Gencheva M, Yen Y, Shively JE, Gaur RK. Mechanistic control of carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) splice isoforms by the heterogeneous nuclear ribonuclear proteins hnRNP L, hnRNP A1, and hnRNP M. J Biol Chem. 2011;286:16039–51.
Sun G, Zhou H, Chen K, Zeng J, Zhang Y, Yan L, et al. HnRNP A1 - mediated alternative splicing of CCDC50 contributes to cancer progression of clear cell renal cell carcinoma via ZNF395. J Exp Clin Cancer Res. 2020;39:116.
Ajiro M, Tang S, Doorbar J, Zheng ZM. Serine/Arginine-rich splicing factor 3 and heterogeneous nuclear ribonucleoprotein a1 regulate alternative RNA splicing and gene expression of human papillomavirus 18 through two functionally distinguishable cis elements. J Virol. 2016;90:9138–52.
Cheunim T, Zhang J, Milligan SG, McPhillips MG, Graham SV. The alternative splicing factor hnRNP A1 is up-regulated during virus-infected epithelial cell differentiation and binds the human papillomavirus type 16 late regulatory element. Virus Res. 2008;131:189–98.
Zheng Y, Jonsson J, Hao C, Shoja Chaghervand S, Cui X, Kajitani N, et al. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and hnRNP A2 inhibit splicing to human papillomavirus 16 splice site SA409 through a UAG-containing sequence in the E7 coding region. J Virol. 2020;94:e01509–20.
Yu C, Guo J, Liu Y, Jia J, Jia R, Fan M. Oral squamous cancer cell exploits hnRNP A1 to regulate cell cycle and proliferation. J Cell Physiol. 2015;230:2252–61.
Loh TJ, Moon H, Cho S, Jang H, Liu YC, Tai H, et al. CD44 alternative splicing and hnRNP A1 expression are associated with the metastasis of breast cancer. Oncol Rep. 2015;34:1231–8.
Clower CV, Chatterjee D, Wang Z, Cantley LC, Vander Heiden MG, Krainer AR. The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc Natl Acad Sci USA 2010;107:1894–9.
Yan Q, Zeng P, Zhou X, Zhao X, Chen R, Qiao J, et al. RBMX suppresses tumorigenicity and progression of bladder cancer by interacting with the hnRNP A1 protein to regulate PKM alternative splicing. Oncogene. 2021;40:2635–50.
Fu R, Yang P, Amin S, Li Z. A novel miR-206/hnRNPA1/PKM2 axis reshapes the Warburg effect to suppress colon cancer growth. Biochem Biophys Res Commun. 2020;531:465–71.
Lan Z, Yao X, Sun K, Li A, Liu S, Wang X. The interaction between lncRNA SNHG6 and hnRNPA1 contributes to the growth of colorectal cancer by enhancing aerobic glycolysis through the regulation of alternative splicing of PKM. Front Oncol. 2020;10:363.
Ferino A, Marquevielle J, Choudhary H, Cinque G, Robert C, Bourdoncle A, et al. hnRNPA1/UP1 unfolds KRAS G-quadruplexes and feeds a regulatory axis controlling gene expression. ACS omega. 2021;6:34092–106.
Cogoi S, Rapozzi V, Cauci S, Xodo LE. Critical role of hnRNP A1 in activating KRAS transcription in pancreatic cancer cells: A molecular mechanism involving G4 DNA. Biochimica et biophysica acta Gen Subj. 2017;1861:1389–98.
Charpentier M, Dupre E, Fortun A, Briand F, Maillasson M, Com E, et al. hnRNP-A1 binds to the IRES of MELOE-1 antigen to promote MELOE-1 translation in stressed melanoma cells. Mol Oncol. 2022;16:594–606.
Yang Z, Chang YJ, Miyamoto H, Yeh S, Yao JL, di Sant’Agnese PA, et al. Suppression of androgen receptor transactivation and prostate cancer cell growth by heterogeneous nuclear ribonucleoprotein A1 via interaction with androgen receptor coregulator ARA54. Endocrinology. 2007;148:1340–9.
Dou R, Liu K, Yang C, Zheng J, Shi D, Lin X, et al. EMT-cancer cells-derived exosomal miR-27b-3p promotes circulating tumour cells-mediated metastasis by modulating vascular permeability in colorectal cancer. Clin Transl Med. 2021;11:e595.
Zhang H, Wang M, He Y, Deng T, Liu R, Wang W, et al. Chemotoxicity-induced exosomal lncFERO regulates ferroptosis and stemness in gastric cancer stem cells. Cell Death Dis. 2021;12:1116.
Zhang H, Deng T, Liu R, Ning T, Yang H, Liu D, et al. CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer. Mol Cancer. 2020;19:43.
Li Y, Zhang J, Li S, Guo C, Li Q, Zhang X, et al. Heterogeneous Nuclear Ribonucleoprotein A1 Loads Batched Tumor-Promoting MicroRNAs Into Small Extracellular Vesicles With the Assist of Caveolin-1 in A549 Cells. Front cell developmental Biol. 2021;9:687912.
Chen C, Zheng H, Luo Y, Kong Y, An M, Li Y, et al. SUMOylation promotes extracellular vesicle-mediated transmission of lncRNA ELNAT1 and lymph node metastasis in bladder cancer. J Clin Invest. 2021;131:e146431.
Qin X, Guo H, Wang X, Zhu X, Yan M, Wang X, et al. Exosomal miR-196a derived from cancer-associated fibroblasts confers cisplatin resistance in head and neck cancer through targeting CDKN1B and ING5. Genome Biol. 2019;20:12.
Zhang M, Sun Y, Huang CP, Luo J, Zhang L, Meng J, et al. Targeting the Lnc-OPHN1-5/androgen receptor/hnRNPA1 complex increases Enzalutamide sensitivity to better suppress prostate cancer progression. Cell Death Dis. 2021;12:855.
Hao A, Wang Y, Zhang X, Li J, Li Y, Li D, et al. Long non-coding antisense RNA HYOU1-AS is essential to human breast cancer development through competitive binding hnRNPA1 to promote HYOU1 expression. Biochimica et biophysica acta Mol cell Res. 2021;1868:118951.
Ren X, Chen C, Luo Y, Liu M, Li Y, Zheng S, et al. lncRNA-PLACT1 sustains activation of NF-kappaB pathway through a positive feedback loop with IkappaBalpha/E2F1 axis in pancreatic cancer. Mol Cancer. 2020;19:35.
Rodriguez-Aguayo C, Monroig PDC, Redis RS, Bayraktar E, Almeida MI, Ivan C, et al. Regulation of hnRNPA1 by microRNAs controls the miR-18a-K-RAS axis in chemotherapy-resistant ovarian cancer. Cell Discov. 2017;3:17029.
Carabet LA, Leblanc E, Lallous N, Morin H, Ghaidi F, Lee J, et al. Computer-aided discovery of small molecules targeting the RNA splicing activity of hnRNP A1 in castration-resistant prostate cancer. Molecules. 2019;24:763.
Ko CC, Chen YJ, Chen CT, Liu YC, Cheng FC, Hsu KC, et al. Chemical proteomics identifies heterogeneous nuclear ribonucleoprotein (hnRNP) A1 as the molecular target of quercetin in its anti-cancer effects in PC-3 cells. J Biol Chem. 2014;289:22078–89.
Jiang R, Su G, Chen X, Chen S, Li Q, Xie B, et al. Esculetin inhibits endometrial cancer proliferation and promotes apoptosis via hnRNPA1 to downregulate BCLXL and XIAP. Cancer Lett. 2021;521:308–21.
Li S, Wang W, Ding H, Xu H, Zhao Q, Li J, et al. Aptamer BC15 against heterogeneous nuclear ribonucleoprotein A1 has potential value in diagnosis and therapy of hepatocarcinoma. Nucleic Acid Ther. 2012;22:391–8.
Huang X, Chen Y, Yi J, Yi P, Jia J, Liao Y, et al. Tetracaine hydrochloride induces cell cycle arrest in melanoma by downregulating hnRNPA1. Toxicol Appl Pharm. 2022;434:115810.
Hatfield JT, Rothnagel JA, Smith R. Characterization of the mouse hnRNP A2/B1/B0 gene and identification of processed pseudogenes. Gene. 2002;295:33–42.
Nguyen ED, Balas MM, Griffin AM, Roberts JT, Johnson AM. Global profiling of hnRNP A2/B1-RNA binding on chromatin highlights LncRNA interactions. RNA Biol. 2018;15:901–13.
Han SP, Friend LR, Carson JH, Korza G, Barbarese E, Maggipinto M, et al. Differential subcellular distributions and trafficking functions of hnRNP A2/B1 spliceoforms. Traffic. 2010;11:886–98.
Montuenga LM, Zhou J, Avis I, Vos M, Martinez A, Cuttitta F, et al. Expression of heterogeneous nuclear ribonucleoprotein A2/B1 changes with critical stages of mammalian lung development. Am J Respir Cell Mol Biol. 1998;19:554–62.
Tauler J, Zudaire E, Liu H, Shih J, Mulshine JL. hnRNP A2/B1 modulates epithelial-mesenchymal transition in lung cancer cell lines. Cancer Res. 2010;70:7137–47.
Katsimpoula S, Patrinou-Georgoula M, Makrilia N, Dimakou K, Guialis A, Orfanidou D, et al. Overexpression of hnRNPA2/B1 in bronchoscopic specimens: a potential early detection marker in lung cancer. Anticancer Res. 2009;29:1373–82.
Fielding P, Turnbull L, Prime W, Walshaw M, Field JK. Heterogeneous nuclear ribonucleoprotein A2/B1 up-regulation in bronchial lavage specimens: a clinical marker of early lung cancer detection. Clin Cancer Res. 1999;5:4048–52.
Wu S, Sato M, Endo C, Sakurada A, Dong B, Aikawa H, et al. hnRNP B1 protein may be a possible prognostic factor in squamous cell carcinoma of the lung. Lung Cancer. 2003;41:179–86.
Cui H, Wu F, Sun Y, Fan G, Wang Q. Up-regulation and subcellular localization of hnRNP A2/B1 in the development of hepatocellular carcinoma. BMC Cancer. 2010;10:356.
Golan-Gerstl R, Cohen M, Shilo A, Suh SS, Bakacs A, Coppola L, et al. Splicing factor hnRNP A2/B1 regulates tumor suppressor gene splicing and is an oncogenic driver in glioblastoma. Cancer Res. 2011;71:4464–72.
Jing GJ, Xu DH, Shi SL, Li QF, Wang SY, Wu FY, et al. Aberrant expression and localization of hnRNP-A2/B1 is a common event in human gastric adenocarcinoma. J Gastroenterol Hepatol. 2011;26:108–15.
Barcelo C, Etchin J, Mansour MR, Sanda T, Ginesta MM, Sanchez-Arevalo Lobo VJ, et al. Ribonucleoprotein HNRNPA2B1 interacts with and regulates oncogenic KRAS in pancreatic ductal adenocarcinoma cells. Gastroenterology. 2014;147:882–92 e888.
Gu WJ, Liu HL. Induction of pancreatic cancer cell apoptosis, invasion, migration, and enhancement of chemotherapy sensitivity of gemcitabine, 5-FU, and oxaliplatin by hnRNP A2/B1 siRNA. Anticancer Drugs. 2013;24:566–76.
Shi X, Ran L, Liu Y, Zhong SH, Zhou PP, Liao MX, et al. Knockdown of hnRNP A2/B1 inhibits cell proliferation, invasion and cell cycle triggering apoptosis in cervical cancer via PI3K/AKT signaling pathway. Oncol Rep. 2018;39:939–50.
Jiang F, Tang X, Tang C, Hua Z, Ke M, Wang C, et al. HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA. J Hematol Oncol. 2021;14:54.
Kim MK, Choi MJ, Lee HM, Choi HS, Park YK, Ryu CJ. Heterogeneous nuclear ribonucleoprotein A2/B1 regulates the ERK and p53/HDM2 signaling pathways to promote the survival, proliferation and migration of nonsmall cell lung cancer cells. Oncol Rep. 2021;46:153.
Rong L, Xu Y, Zhang K, Jin L, Liu X. HNRNPA2B1 inhibited SFRP2 and activated Wnt-beta/catenin via m6A-mediated miR-106b-5p processing to aggravate stemness in lung adenocarcinoma. Pathol Res Pract. 2022;233:153794.
Dai S, Zhang J, Huang S, Lou B, Fang B, Ye T, et al. HNRNPA2B1 regulates the epithelial-mesenchymal transition in pancreatic cancer cells through the ERK/snail signalling pathway. Cancer Cell Int. 2017;17:12.
Yin M, Cheng M, Liu C, Wu K, Xiong W, Fang J, et al. HNRNPA2B1 as a trigger of RNA switch modulates the miRNA-mediated regulation of CDK6. iScience. 2021;24:103345.
Li K, Chen J, Lou X, Li Y, Qian B, Xu D, et al. HNRNPA2B1 affects the prognosis of esophageal cancer by regulating the miR-17-92 Cluster. Front Cell Dev Biol. 2021;9:658642.
Yang Y, Wei Q, Tang Y, Yuanyuan W, Luo Q, Zhao H, et al. Loss of hnRNPA2B1 inhibits malignant capability and promotes apoptosis via down-regulating Lin28B expression in ovarian cancer. Cancer Lett. 2020;475:43–52.
Xuan Y, Wang J, Ban L, Lu JJ, Yi C, Li Z, et al. hnRNPA2/B1 activates cyclooxygenase-2 and promotes tumor growth in human lung cancers. Mol Oncol. 2016;10:610–24.
Liu Y, Zhang H, Li X, Zhang C, Huang H. Identification of anti-tumoral feedback loop between VHLalpha and hnRNPA2B1 in renal cancer. Cell Death Dis. 2020;11:688.
Li X, Johansson C, Glahder J, Mossberg AK, Schwartz S. Suppression of HPV-16 late L1 5’-splice site SD3632 by binding of hnRNP D proteins and hnRNP A2/B1 to upstream AUAGUA RNA motifs. Nucleic Acids Res. 2013;41:10488–508.
Gupta A, Yadav S, Pt A, Mishra J, Samaiya A, Panday RK, et al. The HNRNPA2B1-MST1R-Akt axis contributes to epithelial-to-mesenchymal transition in head and neck cancer. Lab Invest. 2020;100:1589–601.
Moran-Jones K, Grindlay J, Jones M, Smith R, Norman JC. hnRNP A2 regulates alternative mRNA splicing of TP53INP2 to control invasive cell migration. Cancer Res. 2009;69:9219–27.
Peng WZ, Zhao J, Liu X, Li CF, Si S, Ma R. hnRNPA2B1 regulates the alternative splicing of BIRC5 to promote gastric cancer progression. Cancer Cell Int. 2021;21:281.
Shilo A, Ben Hur V, Denichenko P, Stein I, Pikarsky E, Rauch J, et al. Splicing factor hnRNP A2 activates the Ras-MAPK-ERK pathway by controlling A-Raf splicing in hepatocellular carcinoma development. RNA. 2014;20:505–15.
Lee DH, Chung K, Song JA, Kim TH, Kang H, Huh JH, et al. Proteomic identification of paclitaxel-resistance associated hnRNP A2 and GDI 2 proteins in human ovarian cancer cells. J Proteome Res. 2010;9:5668–76.
Zhou J, Allred DC, Avis I, Martinez A, Vos MD, Smith L, et al. Differential expression of the early lung cancer detection marker, heterogeneous nuclear ribonucleoprotein-A2/B1 (hnRNP-A2/B1) in normal breast and neoplastic breast cancer. Breast Cancer Res Treat. 2001;66:217–24.
Santarosa M, Del Col L, Viel A, Bivi N, D’Ambrosio C, Scaloni A, et al. BRCA1 modulates the expression of hnRNPA2B1 and KHSRP. Cell cycle. 2010;9:4666–73.
Ma Y, Yang L, Li R. HnRNPA2/B1 is a novel prognostic biomarker for breast cancer patients. Genet Test Mol Biomark. 2020;24:701–7.
Singh R, Gupta SC, Peng WX, Zhou N, Pochampally R, Atfi A, et al. Regulation of alternative splicing of Bcl-x by BC200 contributes to breast cancer pathogenesis. Cell Death Dis. 2016;7:e2262.
Gao LB, Zhu XL, Shi JX, Yang L, Xu ZQ, Shi SL. HnRNPA2B1 promotes the proliferation of breast cancer MCF-7 cells via the STAT3 pathway. J Cell Biochem. 2021;122:472–84.
Petri BJ, Piell KM, South Whitt GC, Wilt AE, Poulton CC, Lehman NL, et al. HNRNPA2B1 regulates tamoxifen- and fulvestrant-sensitivity and hallmarks of endocrine resistance in breast cancer cells. Cancer Lett. 2021;518:152–68.
Liu Y, Li H, Liu F, Gao LB, Han R, Chen C, et al. Heterogeneous nuclear ribonucleoprotein A2/B1 is a negative regulator of human breast cancer metastasis by maintaining the balance of multiple genes and pathways. EBioMedicine. 2020;51:102583.
Hung CY, Wang YC, Chuang JY, Young MJ, Liaw H, Chang WC, et al. Nm23-H1-stabilized hnRNPA2/B1 promotes internal ribosomal entry site (IRES)-mediated translation of Sp1 in the lung cancer progression. Sci Rep. 2017;7:9166.
Wang JM, Liu BQ, Zhang Q, Hao L, Li C, Yan J, et al. ISG15 suppresses translation of ABCC2 via ISGylation of hnRNPA2B1 and enhances drug sensitivity in cisplatin resistant ovarian cancer cells. Biochimica et biophysica acta Mol cell Res. 2020;1867:118647.
Brandi J, Cecconi D, Cordani M, Torrens-Mas M, Pacchiana R, Dalla Pozza E, et al. The antioxidant uncoupling protein 2 stimulates hnRNPA2/B1, GLUT1 and PKM2 expression and sensitizes pancreas cancer cells to glycolysis inhibition. Free Radic Biol Med. 2016;101:305–16.
Chen ZY, Cai L, Zhu J, Chen M, Chen J, Li ZH, et al. Fyn requires HnRNPA2B1 and Sam68 to synergistically regulate apoptosis in pancreatic cancer. Carcinogenesis. 2011;32:1419–26.
Chen Z, Chen X, Lei T, Gu Y, Gu J, Huang J, et al. Integrative Analysis of NSCLC Identifies LINC01234 as an Oncogenic lncRNA that Interacts with HNRNPA2B1 and Regulates miR-106b Biogenesis. Mol Ther. 2020;28:1479–93.
Meng LD, Shi GD, Ge WL, Huang XM, Chen Q, Yuan H, et al. Linc01232 promotes the metastasis of pancreatic cancer by suppressing the ubiquitin-mediated degradation of HNRNPA2B1 and activating the A-Raf-induced MAPK/ERK signaling pathway. Cancer Lett. 2020;494:107–20.
Zhang Y, Huang W, Yuan Y, Li J, Wu J, Yu J, et al. Long non-coding RNA H19 promotes colorectal cancer metastasis via binding to hnRNPA2B1. J Exp Clin Cancer Res. 2020;39:141.
Liu X, Liu Y, Liu Z, Lin C, Meng F, Xu L, et al. CircMYH9 drives colorectal cancer growth by regulating serine metabolism and redox homeostasis in a p53-dependent manner. Mol Cancer. 2021;20:114.
Lei Y, Guo W, Chen B, Chen L, Gong J, Li W. Tumorreleased lncRNA H19 promotes gefitinib resistance via packaging into exosomes in nonsmall cell lung cancer. Oncol Rep. 2018;40:3438–46.
Fabbiano F, Corsi J, Gurrieri E, Trevisan C, Notarangelo M, D’Agostino VG. RNA packaging into extracellular vesicles: An orchestra of RNA-binding proteins? J Extracell vesicles. 2020;10:e12043.
Chen C, Luo Y, He W, Zhao Y, Kong Y, Liu H, et al. Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer. J Clin Invest. 2020;130:404–21.
Li C, Qin F, Wang W, Ni Y, Gao M, Guo M, et al. hnRNPA2B1-mediated extracellular vesicles sorting of miR-122-5p potentially promotes lung cancer progression. Int J Mol Sci. 2021;22:12866.
Zhao S, Mi Y, Guan B, Zheng B, Wei P, Gu Y, et al. Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer. J Hematol Oncol. 2020;13:156.
Wang J, Du X, Wang X, Xiao H, Jing N, Xue W, et al. Tumor-derived miR-378a-3p-containing extracellular vesicles promote osteolysis by activating the Dyrk1a/Nfatc1/Angptl2 axis for bone metastasis. Cancer Lett. 2022;526:76–90.
Makhafola TJ, Mbele M, Yacqub-Usman K, Hendren A, Haigh DB, Blackley Z, et al. Apoptosis in cancer cells is induced by alternative splicing of hnRNPA2/B1 through splicing of Bcl-x, a mechanism that can be stimulated by an extract of the South African Medicinal Plant, Cotyledon orbiculata. Front Oncol. 2020;10:547392.
Sudhakaran M, Parra MR, Stoub H, Gallo KA, Doseff AI. Apigenin by targeting hnRNPA2 sensitizes triple-negative breast cancer spheroids to doxorubicin-induced apoptosis and regulates expression of ABCC4 and ABCG2 drug efflux transporters. Biochem Pharm. 2020;182:114259.
Li H, Guo L, Huang A, Xu H, Liu X, Ding H, et al. Nanoparticle-conjugated aptamer targeting hnRNP A2/B1 can recognize multiple tumor cells and inhibit their proliferation. Biomaterials. 2015;63:168–76.
Ikeda K, Kamisuki S, Uetake S, Mizusawa A, Ota N, Sasaki T, et al. Ridaifen G, tamoxifen analog, is a potent anticancer drug working through a combinatorial association with multiple cellular factors. Bioorg Med Chem. 2015;23:6118–24.
Papadopoulou C, Boukakis G, Ganou V, Patrinou-Georgoula M, Guialis A. Expression profile and interactions of hnRNP A3 within hnRNP/mRNP complexes in mammals. Arch Biochem Biophys. 2012;523:151–60.
Ma AS, Moran-Jones K, Shan J, Munro TP, Snee MJ, Hoek KS, et al. Heterogeneous nuclear ribonucleoprotein A3, a novel RNA trafficking response element-binding protein. J Biol Chem. 2002;277:18010–20.
Tanaka E, Fukuda H, Nakashima K, Tsuchiya N, Seimiya H, Nakagama H. HnRNP A3 binds to and protects mammalian telomeric repeats in vitro. Biochem Biophys Res Commun. 2007;358:608–14.
Katahira J, Miki T, Takano K, Maruhashi M, Uchikawa M, Tachibana T, et al. Nuclear RNA export factor 7 is localized in processing bodies and neuronal RNA granules through interactions with shuttling hnRNPs. Nucleic Acids Res. 2008;36:616–28.
Comegna M, Succoio M, Napolitano M, Vitale M, D’Ambrosio C, Scaloni A, et al. Identification of miR-494 direct targets involved in senescence of human diploid fibroblasts. FASEB J. 2014;28:3720–33.
Chen X, Lloyd SM, Kweon J, Gamalong GM, Bao X. Epidermal progenitors suppress GRHL3-mediated differentiation through intronic polyadenylation promoted by CPSF-HNRNPA3 collaboration. Nat Commun. 2021;12:448.
Nihei Y, Mori K, Werner G, Arzberger T, Zhou Q, Khosravi B, et al. Poly-glycine-alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3. Acta Neuropathol. 2020;139:99–118.
Ren X, Dong Y, Duan M, Zhang H, Gao P. Abnormal expression of HNRNPA3 in multistep hepatocarcinogenesis. Oncol Lett. 2021;21:46.
Shi H, Hood KA, Hayes MT, Stubbs RS. Proteomic analysis of advanced colorectal cancer by laser capture microdissection and two-dimensional difference gel electrophoresis. J Proteom. 2011;75:339–51.
Amano N, Matsumoto K, Shimizu Y, Nakamura M, Tsumura H, Ishii D, et al. High HNRNPA3 expression is associated with lymph node metastasis and poor prognosis in patients treated with radical cystectomy. Urol Oncol. 2021;39:196 e191–196 e197.
Taoka Y, Matsumoto K, Ohashi K, Minamida S, Hagiwara M, Nagi S, et al. Protein expression profile related to cisplatin resistance in bladder cancer cell lines detected by two-dimensional gel electrophoresis. Biomed Res. 2015;36:253–61.
Yi GZ, Xiang W, Feng WY, Chen ZY, Li YM, Deng SZ, et al. Identification of Key Candidate Proteins and Pathways Associated with Temozolomide Resistance in Glioblastoma Based on Subcellular Proteomics and Bioinformatical Analysis. Biomed Res Int. 2018;2018:5238760.
Xing S, Wang Y, Hu K, Wang F, Sun T, Li Q. WGCNA reveals key gene modules regulated by the combined treatment of colon cancer with PHY906 and CPT11. Biosci Rep. 2020;40:BSR20200935.
Wang TH, Wu CC, Huang KY, Chuang WY, Hsueh C, Li HJ, et al. Profiling of subcellular EGFR interactome reveals hnRNP A3 modulates nuclear EGFR localization. Oncogenesis. 2020;9:40.
Pacurari M, Addison JB, Bondalapati N, Wan YW, Luo D, Qian Y, et al. The microRNA-200 family targets multiple non-small cell lung cancer prognostic markers in H1299 cells and BEAS-2B cells. Int J Oncol. 2013;43:548–60.
Mishra N, Reddy KS, Timilsina U, Gaur D, Gaur R. Human APOBEC3B interacts with the heterogenous nuclear ribonucleoprotein A3 in cancer cells. J Cell Biochem. 2018;119:6695–703.
Wippel HH, Fioramonte M, Chavez JD, Bruce JE. Deciphering the architecture and interactome of hnRNP proteins and enigmRBPs. Mol omics. 2021;17:503–16.
Honda H, Hamasaki H, Wakamiya T, Koyama S, Suzuki SO, Fujii N, et al. Loss of hnRNPA1 in ALS spinal cord motor neurons with TDP-43-positive inclusions. Neuropathology. 2015;35:37–43.
Guo C, Sun L, Hao S, Huang X, Hu H, Liang D, et al. Monoclonal antibody against H1N1 influenza virus hemagglutinin cross reacts with hnRNPA1 and hnRNPA2/B1. Mol Med Rep. 2020;22:3969–75.
Farg MA, Sundaramoorthy V, Sultana JM, Yang S, Atkinson RA, Levina V, et al. C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet. 2014;23:3579–95.
Bengoechea R, Pittman SK, Tuck EP, True HL, Weihl CC. Myofibrillar disruption and RNA-binding protein aggregation in a mouse model of limb-girdle muscular dystrophy 1D. Hum Mol Genet. 2015;24:6588–602.
Takanashi K, Yamaguchi A. Aggregation of ALS-linked FUS mutant sequesters RNA binding proteins and impairs RNA granules formation. Biochem Biophys Res Commun. 2014;452:600–7.
Torosyan Y, Dobi A, Glasman M, Mezhevaya K, Naga S, Huang W, et al. Role of multi-hnRNP nuclear complex in regulation of tumor suppressor ANXA7 in prostate cancer cells. Oncogene. 2010;29:2457–66.
Cloutier A, Shkreta L, Toutant J, Durand M, Thibault P, Chabot B. hnRNP A1/A2 and Sam68 collaborate with SRSF10 to control the alternative splicing response to oxaliplatin-mediated DNA damage. Sci Rep. 2018;8:2206.
Lemieux B, Blanchette M, Monette A, Mouland AJ, Wellinger RJ, Chabot B. A Function for the hnRNP A1/A2 Proteins in Transcription Elongation. PLoS One. 2015;10:e0126654.
Wu H, Du J, Li C, Li H, Guo H, Li Z. Kaempferol can reverse the 5-Fu resistance of colorectal cancer cells by inhibiting PKM2-mediated glycolysis. Int J Mol Sci. 2022;23:3544.
Chen M, David CJ, Manley JL. Concentration-dependent control of pyruvate kinase M mutually exclusive splicing by hnRNP proteins. Nat Struct Mol Biol. 2012;19:346–54.
Generini S, Steiner G, Miniati I, Conforti ML, Guiducci S, Skriner K, et al. Anti-hnRNP and other autoantibodies in systemic sclerosis with joint involvement. Rheumatol. 2009;48:920–5.
Fang X, Yoon JG, Li L, Tsai YS, Zheng S, Hood L, et al. Landscape of the SOX2 protein-protein interactome. Proteomics. 2011;11:921–34.
Chang Y, Lu X, Qiu J. Compensatory expression regulation of highly homologous proteins HNRNPA1 and HNRNPA2. Turk J Biol. 2021;45:187–95.
Hutchison S, LeBel C, Blanchette M, Chabot B. Distinct sets of adjacent heterogeneous nuclear ribonucleoprotein (hnRNP) A1/A2 binding sites control 5’ splice site selection in the hnRNP A1 mRNA precursor. J Biol Chem. 2002;277:29745–52.
Xu Y, Wu W, Han Q, Wang Y, Li C, Zhang P, et al. Post-translational modification control of RNA-binding protein hnRNPK function. Open Biol. 2019;9:180239.
Zhang Y, Li L, Ye Z, Zhang L, Yao N, Gai L. Identification of m6A methyltransferase-related genes predicts prognosis and immune infiltrates in head and neck squamous cell carcinoma. Ann Transl Med. 2021;9:1554.
Dai L, Li J, Tsay JJ, Yie TA, Munger JS, Pass H, et al. Identification of autoantibodies to ECH1 and HNRNPA2B1 as potential biomarkers in the early detection of lung cancer. Oncoimmunology. 2017;6:e1310359.
Klinge CM, Piell KM, Tooley CS, Rouchka EC. HNRNPA2/B1 is upregulated in endocrine-resistant LCC9 breast cancer cells and alters the miRNA transcriptome when overexpressed in MCF-7 cells. Sci Rep. 2019;9:9430.
Guo H, Wang B, Xu K, Nie L, Fu Y, Wang Z, et al. m(6)A Reader HNRNPA2B1 Promotes Esophageal Cancer Progression via Up-Regulation of ACLY and ACC1. Front Oncol. 2020;10:553045.
Chen Y, Liu J, Wang W, Xiang L, Wang J, Liu S, et al. High expression of hnRNPA1 promotes cell invasion by inducing EMT in gastric cancer. Oncol Rep. 2018;39:1693–701.
Ji E, Lee H, Ahn S, Jung M, Lee SH, Lee JH, et al. Heterogeneous nuclear ribonucleoprotein A1 promotes the expression of autophagy-related protein 6 in human colorectal cancer. Biochem Biophys Res Commun. 2019;513:255–60.
Liu H, Li D, Sun L, Qin H, Fan A, Meng L, et al. Interaction of lncRNA MIR100HG with hnRNPA2B1 facilitates m(6)A-dependent stabilization of TCF7L2 mRNA and colorectal cancer progression. Mol Cancer. 2022;21:74.
Tang J, Chen Z, Wang Q, Hao W, Gao WQ, Xu H. hnRNPA2B1 promotes colon cancer progression via the MAPK pathway. Front Genet. 2021;12:666451.
Gu W, Liu W, Shen X, Shi Y, Wang L, Liu H. Emergence of heterogeneous nuclear ribonucleoprotein A2/B1 vs loss of E-cadherin: their reciprocal immunoexpression profiles in human pancreatic cancer. Ann Diagn Pathol. 2013;17:14–17.
Liu J, Sun G, Pan S, Qin M, Ouyang R, Li Z, et al. The cancer genome atlas (TCGA) based m(6)A methylation-related genes predict prognosis in hepatocellular carcinoma. Bioengineered. 2020;11:759–68.
Moller K, Wecker AL, Hoflmayer D, Fraune C, Makrypidi-Fraune G, Hube-Magg C, et al. Upregulation of the heterogeneous nuclear ribonucleoprotein hnRNPA1 is an independent predictor of early biochemical recurrence in TMPRSS2:ERG fusion-negative prostate cancers. Virchows Arch. 2020;477:625–36.
Lage-Vickers S, Sanchis P, Bizzotto J, Toro A, Sabater A, Lavignolle R, et al. Exploiting interdata relationships in prostate cancer proteomes: clinical significance of HO-1 interactors. Antioxidants. 2022;11:290.
Zhang C, Liu J, Guo H, Hong D, Ji J, Zhang Q, et al. m6A RNA methylation regulators were associated with the malignancy and prognosis of ovarian cancer. Bioengineered. 2021;12:3159–76.
Jin Y, Wang Z, He D, Zhu Y, Hu X, Gong L, et al. Analysis of m6A-related signatures in the tumor immune microenvironment and identification of clinical prognostic regulators in adrenocortical carcinoma. Front Immunol. 2021;12:637933.
Gu Z, Xia J, Xu H, Frech I, Tricot G, Zhan F. NEK2 promotes aerobic glycolysis in multiple myeloma through regulating splicing of pyruvate kinase. J Hematol Oncol. 2017;10:17.
Zhang D, Tao L, Xu N, Lu X, Wang J, He G, et al. CircRNA circTIAM1 promotes papillary thyroid cancer progression through the miR-646/HNRNPA1 signaling pathway. Cell death Discov. 2022;8:21.
Zerbe LK, Pino I, Pio R, Cosper PF, Dwyer-Nield LD, Meyer AM, et al. Relative amounts of antagonistic splicing factors, hnRNP A1 and ASF/SF2, change during neoplastic lung growth: implications for pre-mRNA processing. Mol Carcinog. 2004;41:187–96.
Wang Z, Lin M, He L, Qi H, Shen J, Ying K. Exosomal lncRNA SCIRT/miR-665 transferring promotes lung cancer cell metastasis through the inhibition of HEYL. J Oncol. 2021;2021:9813773.
Li H, Cui Z, Lv X, Li J, Gao M, Yang Z, et al. Long non-coding RNA HOTAIR function as a competing endogenous RNA for miR-149-5p to promote the cell growth, migration, and invasion in non-small cell lung cancer. Front Oncol. 2020;10:528520.
Yu PF, Kang AR, Jing LJ, Wang YM. Long non-coding RNA CACNA1G-AS1 promotes cell migration, invasion and epithelial-mesenchymal transition by HNRNPA2B1 in non-small cell lung cancer. Eur Rev Med Pharm Sci. 2018;22:993–1002.
Yao A, Xiang Y, Si YR, Fan LJ, Li JP, Li H, et al. PKM2 promotes glucose metabolism through a let-7a-5p/Stat3/hnRNP-A1 regulatory feedback loop in breast cancer cells. J Cell Biochem. 2019;120:6542–54.
Zhu W, Tan L, Ma T, Yin Z, Gao J. Long noncoding RNA SNHG8 promotes chemoresistance in gastric cancer via binding with hnRNPA1 and stabilizing TROY expression. Dig Liver Dis. 2022;S1590–8658.
Chen FR, Sha SM, Wang SH, Shi HT, Dong L, Liu D, et al. RP11-81H3.2 promotes gastric cancer progression through miR-339-HNRNPA1 interaction network. Cancer Med. 2020;9:2524–34.
Zhou B, Wang Y, Jiang J, Jiang H, Song J, Han T, et al. The long noncoding RNA colon cancer-associated transcript-1/miR-490 axis regulates gastric cancer cell migration by targeting hnRNPA1. IUBMB life. 2016;68:201–10.
Wu H, Cui M, Li C, Li H, Dai Y, Cui K, et al. Kaempferol reverses aerobic glycolysis via miR-339-5p-mediated PKM alternative splicing in colon cancer cells. J Agric Food Chem. 2021;69:3060–8.
Fujiya M, Konishi H, Mohamed Kamel MK, Ueno N, Inaba Y, Moriichi K, et al. microRNA-18a induces apoptosis in colon cancer cells via the autophagolysosomal degradation of oncogenic heterogeneous nuclear ribonucleoprotein A1. Oncogene. 2014;33:4847–56.
Konishi H, Fujiya M, Ueno N, Moriichi K, Sasajima J, Ikuta K, et al. microRNA-26a and -584 inhibit the colorectal cancer progression through inhibition of the binding of hnRNP A1-CDK6 mRNA. Biochem Biophys Res Commun. 2015;467:847–52.
Sun Y, Luo M, Chang G, Ren W, Wu K, Li X, et al. Phosphorylation of Ser6 in hnRNPA1 by S6K2 regulates glucose metabolism and cell growth in colorectal cancer. Oncol Lett. 2017;14:7323–31.
Wu Y, Yang X, Chen Z, Tian L, Jiang G, Chen F, et al. m(6)A-induced lncRNA RP11 triggers the dissemination of colorectal cancer cells via upregulation of Zeb1. Mol Cancer. 2019;18:87.
Luo J, Zheng J, Hao W, Zeng H, Zhang Z, Shao G. lncRNA PCAT6 facilitates cell proliferation and invasion via regulating the miR-326/hnRNPA2B1 axis in liver cancer. Oncol Lett. 2021;21:471.
Chen T, Gu C, Xue C, Yang T, Zhong Y, Liu S, et al. LncRNA-uc002mbe.2 interacting with hnRNPA2B1 mediates AKT deactivation and p21 up-regulation induced by trichostatin in liver cancer cells. Front Pharm. 2017;8:669.
Stockley J, Villasevil ME, Nixon C, Ahmad I, Leung HY, Rajan P. The RNA-binding protein hnRNPA2 regulates beta-catenin protein expression and is overexpressed in prostate cancer. RNA Biol. 2014;11:755–65.
Han X, Xiang X, Yang H, Zhang H, Liang S, Wei J, et al. p300-catalyzed lysine crotonylation promotes the proliferation, invasion, and migration of hela cells via heterogeneous nuclear ribonucleoprotein A1. Anal Cell Pathol. 2020;2020:5632342.
Rosenberger S, De-Castro Arce J, Langbein L, Steenbergen RD, Rosl F. Alternative splicing of human papillomavirus type-16 E6/E6* early mRNA is coupled to EGF signaling via Erk1/2 activation. Proc Natl Acad Sci USA. 2010;107:7006–11.
Zheng H, Chen C, Luo Y, Yu M, He W, An M, et al. Tumor-derived exosomal BCYRN1 activates WNT5A/VEGF-C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancer. Clin Transl Med. 2021;11:e497.
Zeng J, Xu H, Huang C, Sun Y, Xiao H, Yu G, et al. CD46 splice variant enhances translation of specific mRNAs linked to an aggressive tumor cell phenotype in bladder cancer. Mol Ther Nucleic Acids. 2021;24:140–53.
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This work was supported by the Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant No. KYCX21_1568).
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JF and JW designed the study. YL, XW and QG reviewed the literature and wrote the manuscript. JW and YS provided assist on painting figures and tables. All authors read and approved the final manuscript.
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Lu, Y., Wang, X., Gu, Q. et al. Heterogeneous nuclear ribonucleoprotein A/B: an emerging group of cancer biomarkers and therapeutic targets. Cell Death Discov. 8, 337 (2022). https://doi.org/10.1038/s41420-022-01129-8
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DOI: https://doi.org/10.1038/s41420-022-01129-8
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