Abstract
MicroRNA-98 (miR-98) stands as an important molecule in the intricate landscape of oncology. As a subset of microRNAs, these small non-coding RNAs have accompanied a new era in cancer research, underpinning their significant roles in tumorigenesis, metastasis, and therapeutic interventions. This review provides a comprehensive insight into the biogenesis, molecular properties, and physiological undertakings of miR-98, highlighting its double-edged role in cancer progression—acting both as a tumor promoter and suppressor. Intriguingly, miR-98 has profound implications for various aspects of cancer progression, modulating key cellular functions, including proliferation, apoptosis, and the cell cycle. Given its expression patterns, the potential of miR-98 as a diagnostic and prognostic biomarker, especially in liquid biopsies and tumor tissues, is explored, emphasizing the hurdles in translating these findings clinically. The review concludes by evaluating therapeutic avenues to modulate miR-98 expression, addressing the challenges in therapy resistance, and assessing the efficacy of miR-98 interventions. In conclusion, while miR-98’s involvement in cancer showcases promising diagnostic and therapeutic avenues, future research should pivot towards understanding its role in tumor-stroma interactions, immune modulation, and metabolic regulation, thereby unlocking novel strategies for cancer management.
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Introduction
Cancer remains a significant global health issue due to its increasing cases and high mortality [1]. Despite progress in cancer research and improved detection and treatment methods, it continues to cause major societal and economic burdens [2]. Research is now focused on finding new biomarkers for early diagnosis and prognosis, as well as identifying potential therapeutic molecular targets. Non-coding RNAs (ncRNAs), including microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA), have emerged as significant epigenetic factors in cancer development and progression [3,4,5].
MicroRNAs are small non-coding RNA molecules, typically 19–25 nucleotides in length, that regulate gene expression post-transcriptionally. These molecules play critical roles in numerous biological processes, including cell growth, differentiation, apoptosis, and metabolism [6]. In the context of oncology, miRNAs have garnered significant attention for their intricate roles in tumorigenesis, acting either as oncogenes or tumor suppressors [7]. Dysregulation of miRNAs can impact a wide range of cellular pathways, leading to uncontrolled proliferation, evasion from apoptosis, angiogenesis, and metastasis. Additionally, due to their stability in bodily fluids, miRNAs hold promise as diagnostic and prognostic biomarkers, providing non-invasive tools to monitor disease progression and therapeutic response [8].
Long noncoding RNAs, which are over 200 nucleotides in length and do not encode proteins, are important in regulating transcription and other cellular processes [9, 10]. Circular RNAs, characterized by their unique circular structure and stability, play a role in gene regulation as miRNA sponges and are linked to cancer progression [11]. Their dysregulation can contribute to cancer by acting as oncogenes or tumor suppressors [12].
Among the myriad of miRNAs studied in oncology, miR-98 has risen to prominence owing to its intriguing roles in various human cancers. Initial studies reported differential expression of miR-98 in tumor tissues compared to adjacent normal tissues, hinting at its potential relevance in carcinogenesis. Research unveiled miR-98’s capacity to modulate multiple signaling pathways, influencing tumor growth, metastasis, and therapy resistance.
Several studies have indicated that miR-98 can act as both a tumor suppressor or an oncogene, depending on the cancer type and cellular context. Its multifaceted nature has led researchers to investigate its mechanistic roles and potential as a therapeutic target in greater depth [7].
This review aims to provide a comprehensive overview of the current knowledge surrounding miR-98 in the context of human cancer. We will explore the molecular and cellular mechanisms by which miR-98 contributes to cancer progression, its potential utility as a diagnostic and prognostic biomarker, and the emerging therapeutic strategies targeting this miRNA.
Basics of microRNA-98
Biogenesis and molecular characteristics of miR-98
MiR-98 is an intronic miRNA found on chromosome X (Xp11.22) and one of the twelve members of the let-7 miRNA family [13]. MiR-98 is initially transcribed as primary miRNAs (pri-miRNAs) in the nucleus by RNA polymerase II. Primary miR-98 undergoes processing by the Drosha-DGCR8 complex, resulting in a precursor hairpin structure termed pre-miR-98 [14]. This precursor is then exported to the cytoplasm via Exportin-5, where it is further cleaved by the enzyme Dicer to generate the mature miR-98 molecule (Fig. 1) [15, 16].
The process of miRNA biogenesis. Pre-miRNAs are created after RNAPII transcribes miRNA genes to pri-miRNAs, which are ultimately produced when Drosha cleaves pri-miRNAs. Pre-miRNAs are transferred to the nucleus and into the cytoplasm via Exportin5, where Dicer will turn them into mature miRNAs. The combination of mature miRNAs with AGO2 creates RISCs, which are essential for regulating gene expression
The length of mature miR-98-5p and miR-98-3p is 22 nucleotides [17, 18]. Its specific sequence and secondary structure contribute to its target recognition and binding properties. Notably, the “seed sequence” of miR-98, typically spanning nucleotides 2–8 from its 5’ end, plays a critical role in target mRNA recognition and binding [19].
Mature miRNAs miR-98-5p and miR-98-3p are produced from the opposite arms of the stem-loop of pre-miR-98 (Fig. 2A) [20]. The stability and functionality of these miRNAs vary in their biological characteristics. The “guide strand” miR-98-5p and the “passenger” strand miR-98-3p are produced by the miR-98 hairpin, as shown in Fig. 2B. Deep sequencing data indicates that miR-98-5p is more common than miR-98-3p [18, 21].
(A) miR-98 family sequence structure. (B) It has two mature sequences, hsa-miR-98-5p (MIMAT0000096, miR-98-5p) and hsa-miR-98-3p (MIMAT0022842, miR-98-3p)
The biogenesis of miR-98 can be influenced by various cellular factors and conditions. For example, mutations or alterations in components of the Drosha or Dicer complexes can impact miR-98 maturation [22, 23]. Additionally, external factors like cellular stress or specific signaling pathways can modulate the expression and maturation of miR-98, highlighting the intricate regulatory network governing its biogenesis [24].
Physiological roles of miR-98 in cellular functions
Under normal physiological conditions, miR-98 often plays a role in regulating cellular growth. By targeting specific mRNAs involved in cell cycle progression, miR-98 can fine-tune the balance between proliferation and quiescence. MiR-98 has been implicated in cellular differentiation processes in various tissues [25]. For instance, in neuronal development, miR-98 may modulate the differentiation of neural progenitors into mature neurons by regulating key transcription factors or signaling molecules [26]. Additionally, the balance between cell survival and programmed cell death is crucial for tissue homeostasis. MiR-98 can influence this balance by targeting mRNAs associated with apoptosis, either promoting or inhibiting the process depending on the cellular context [27].
Furthermore, cells often encounter various forms of stress, such as oxidative stress, nutrient deprivation, or DNA damage. MiR-98 contributes to the cellular stress response by modulating the expression of stress-responsive genes, aiding in either cellular adaptation or the initiation of cell death pathways [28]. Emerging evidence suggests that miR-98, like other miRNAs, can be packaged into extracellular vesicles, facilitating intercellular communication. Through this mechanism, miR-98 may influence neighboring or distant cells, impacting tissue function and homeostasis [29].
Functional roles of miR-98 in cancer progression
MiR-98 plays a multifaceted role in cancer progression, exhibiting both oncogenic and tumor-suppressive properties, depending on the cancer context and microenvironment. Its dual role is exemplified by studies showing its contrasting functions in different cancer types (Fig. 3) (Table 1). For instance, while miR-98 suppresses tumor growth in lung cancer, it promotes breast cancer progression [30, 31].
Comprehensive illustration of the interactions between miR-98 and its main target genes
MiR-98 has been identified as having a dual nature in tumorigenesis. Specifically, in certain cancer scenarios, it promotes tumorigenesis, as evidenced by researchers’ findings in gastric cancer, where overexpression of miR-98 led to increased cell growth and unfavorable patient outcomes [75]. This oncogenic potential might be driven by its ability to target and suppress tumor suppressor genes or pathways. Conversely, miR-98 has also been reported to function as a tumor suppressor, such as in hepatocellular carcinoma, where it inhibits oncogenic pathways or directly targets genes that drive tumorigenesis [69].
A variety of epigenetic elements are known to impact miR-98. Notably, current research is largely centered on how non-coding RNAs, such as lncRNA (long non-coding RNA) and circRNA (circular RNA), interact with miR-98 (Fig. 4).
A detailed overview of LncRNAs’ interactions with miR-98 in human malignancies
MiR-98 has profound effects on cancer cell proliferation, apoptosis, and cell cycle regulation, according to research into its role in cellular mechanisms. It can modulate gene expression essential for cell growth, as exemplified by its ability to reduce cell proliferation in colorectal cancer cells, potentially via the IGF1R signaling pathway [98]. Apoptosis, a key mechanism in cancer control, is also influenced by miR-98. In glioma cells, miR-98 has been found to induce apoptosis by targeting the HMGA2 gene [99]. Moreover, its interaction with the cell cycle machinery can determine cell fate, with studies in cervical cancer revealing that its overexpression can induce G1 cell cycle arrest [91].
Furthermore, miR-98 plays a significant role in metastasis and angiogenesis, essential processes in cancer spread and growth. Through the regulation of EMT, miR-98 suppresses EMT and metastasis, as observed in bladder cancer, where it targets the IL-6/STAT3 signaling pathway [100]. Moreover, it can inhibit metastatic dissemination by regulating the degradation of the extracellular matrix, as evident in osteosarcoma, where miR-98 curbs metastasis by targeting MMP2 [101]. In pancreatic cancer, miR-98 has been shown to attenuate angiogenesis by directly targeting VEGFA, underscoring its role in vascular dynamics within tumors [102].
In conclusion, miR-98 emerges as a fundamental player in the complex landscape of cancer progression, dealing with tumorigenesis, cellular mechanisms, metastasis, and. Its role, whether tumor-promoting or tumor-suppressing, is highly dependent on the cancer type and microenvironment, emphasizing the necessity for context-specific therapeutic approaches targeting miR-98 in cancer treatment.
Patterns of miR-98 expression in different cancer types
Breast Cancer (BC)
BC is the most common cancer in women worldwide [103, 104]. At this point, targeted therapy, radiation therapy, chemotherapy, endocrine therapy, and surgical removal are the main methods of treatment [105]. Although the prognosis for breast tumors is improving, the condition is still the primary cause of mortality from cancer in women [103].
In breast cancer tissues and cell lines, miR-98 expression has been frequently reported to be downregulated. This reduced expression is often associated with more aggressive tumor subtypes and poorer patient prognoses. Notably, the level of miR-98 has been inversely correlated with metastatic potential in several breast cancer studies.
Researchers demonstrated the down-regulation of miR-98-5p in tumor tissues and MCF-7 breast cancer cells. Concurrently, they observed an up-regulation of Gab2, which countered by the transfection with miR-98-5p, led to significant inhibition of proliferation, migration, and invasion of MCF-7 cells [32]. Furthermore, other investigators elaborated on the oncogenic nature of Linc01287 that sponge miR-98-5p and the negative regulation of IGF1 by miR-98-5p, respectively. Overexpression of miR-98 or knockdown of Linc01287 resulted in an inhibitory effect on breast cancer cell progression, highlighting a potential therapeutic pathway in breast cancer treatment [33, 106].
The long noncoding RNA SNHG16 promoted breast cancer cell migration by acting as a competitive endogenous RNA (ceRNA) for E2F5 by binding with miR-98, while the miR-98-5p/IGF2 axis affected herceptin sensitivity in HER2 positive breast cancer. Specifically, upregulation of miR-98-5p led to decreased IGF2 expression, hence re-sensitizing herceptin-resistant cells [34, 35].
In a different perspective, experts revealed that submicron silica particles (SM-SiO2s) suppressed growth in various cancer cells, including breast cancer, by regulating the XLOC_001659/miR-98-5p/MAP3K2 pathway, suggesting a broader spectrum of miR-98-5p’s anti-cancer effects [66]. Additionally, it was found that miR-98 hindered proliferation, invasion, and migration while promoting apoptosis in breast cancer cells by targeting HMGA2, emphasizing the significance of miR-98 in controlling multiple facets of cancer progression [37].
Moreover, exploratory studies broadened the scope to lung cancer and the effects of newly synthesized heterosteroids on miRNA expressions in MCF-7 breast cancer cells respectively. It was found that aspirin treatment induced the expression of miR-98, depressing WNT1 in lung cancer cells [38]. It was noted that while tamoxifen up-regulated miR-98 expression, new heterosteroids significantly down-regulated it, suggesting a potential for reducing drug resistance [42].
Comprehensive analyses supported miR-98’s important role in regulating tumor growth, invasion, and angiogenesis by down-regulating ALK4 and MMP11, as well as its potential predictive value as a biomarker in breast cancer patients [39, 43]. A specific study explored the potential of miR-98 in predicting Sentinel Lymph Node Metastasis in ER+/HER2-breast cancer, developing a model that showed a significant association between miR-98 and SLNM, however, the direction of miR-98 regulation wasn’t detailed [106]. Additionally, it was demonstrated that dihydromyricetin could potentiate the efficacy of Herceptin in SKBR3 cells by up-regulating miR-98-5p, hence inhibiting IGF1R/HER2 dimer formation and consequently reversing Herceptin resistance [107].
MiR-98 was discovered to be differentially expressed in the HER2 + subtype across different breast cancer subtypes [108]. Employing algorithms, a regulatory interaction between miR-98 and the CD24 gene in breast cancer was identified, implying that miR-98 may play a functional role via CD24 targeting [40]. Deep sequencing also revealed a decrease in miR-98/Let-7 family miRNA expression in breast tumors compared to normal tissues, which aligns with the transition from noninvasive to invasive carcinomas [109].
The interaction between miR-98 and drug response was discovered, revealing that miR-98, along with other miRNAs, could affect docetaxel sensitivity [110]. Furthermore, estradiol (E2) induced the upregulation of miR-98 and other miRNAs in MCF-7 breast cancer cells, which resulted in a decrease in c-Myc and E2F2 protein levels, demonstrating miR-98’s role in the E2 response pathway in breast cancer scenarios [41]. The potential association of miR-98 with breast cancer was identified using network-based algorithms [111].
Downregulation of miR-98 in breast cancer biology has been linked to aggressive tumor subtypes and adverse patient outcomes. MiR-98 modulation could be beneficial in the treatment of breast cancer by influencing tumor growth, invasion, and drug responses. In addition to breast cancer, miR-98 could possibly be useful in the diagnosis, prognosis, and treatment of other cancers.
Lung cancer
Lung cancer is one of the most common cancers globally and contributes significantly to cancer-related death [112]. Based on their histological features, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) are the two main subtypes of lung carcinoma. The cause of about 85% of lung cancers is NSCLC [113]. Contrastingly, in certain subtypes of lung cancer, particularly non-small cell lung carcinoma (NSCLC), miR-98 has shown elevated expression. This upregulation has been linked to increased tumor growth and resistance to certain therapeutic agents, suggesting an oncogenic role in this context.
A specific study found that aspirin could improve lung cancer by targeting the miR-98/WNT1 axis. This targeted intervention reduced cell viability and formed malignant colonies. In lung cancer cells, aspirin activated miR-98, which decreased WNT1 expression. This discovery illuminates aspirin’s lung cancer treatment mechanism [38]. Similar studies have shown that miR-98 regulates several molecular interactions, including miR-98-5p/TGFBR1, ALG3, and PAK1. These regulatory interactions are crucial to lung cancer cell proliferation, migration, invasion, and apoptosis [45].
Several studies have found miR-98-related molecular networks, including the NEAT1/hsa-miR-98-5p/MAPK6 axis and the XLOC_001659/MAP3K2 pathway. The studies show that miR-98 affects lung cancer progression in a variety of cancer environments [44, 66]. Scientific studies on circular RNAs like circ_0048856 and circ_0006349, as well as interactions between integrin β3 (ITGB3) and miR-98, reveal challenging regulatory mechanisms. These interactions regulate lung cancer pathogenesis, including cisplatin resistance, malignancy, glycolysis, and in vivo tumor formation via targeting ITBG3 and MKP1 [47, 48, 54].
Researchers found a significant inverse relationship between lncRNA ANRIL and miR-98 in lung cancer cells, demonstrating that suppressing ANRIL increases miR-98 expression, preventing cisplatin resistance [114]. Another study found that lncRNA SNHG4 regulates miR-98-5p, affecting lung cancer cell proliferation, migration, and invasiveness [115].
Researchers also noted that miR-98 inhibits TWIST expression, which inhibits NSCLC cell migration and invasion, making it a potential tumor suppressor [46]. Jiang et al. and Ni et al. found that miR-98 modulates TGFBR1 and ITGB3 to inhibit cancer cell proliferation, migration, and invasion [48, 49]. Another study found that increasing miR-98 expression could hinder NSCLC progression by inhibiting the SALL4 protein [50].
Another example of complexity was uncovered in a study that identified a regulatory network involving miR-93, miR-98, and miR-197. These microRNAs impact the expression of the tumor suppressor gene FUS1, and an observed overexpression of miR-93 and miR-98 in small-cell lung cancer was documented [55]. Researchers found that curcumin suppressed lung cancer metastasis by increasing miR-98 expression, which downregulated LIN28A, MMP2, and MMP9 [55]. In another study, thiostrepton, an anti-cancer stem cell agent, increased tumor suppressor miR-98 levels to inhibit NSCLC cell growth and improve chemotherapy efficacy when combined with gemcitabine [52].
Researchers found that miR-98-3p was the least expressed dysregulated exosomal miRNA in lung adenocarcinoma (LUAD) patients. Although exosomal miR-7977 was the main focus as a novel biomarker for LUAD, LUAD patients had lower serum miR-98-3p than controls [116].
The researchers discovered that using a mimic to upregulate miR-98-5p reduced cell proliferation and increased apoptosis in NSCLC cells by targeting MAP4K3, indicating a potential pathway for suppressing NSCLC progression [50]. Another study found that the circular RNA hsa_circ_0003489 affects the resistance to paclitaxel in NSCLC through the miR-98-5p/IGF2 axis. Inhibiting hsa_circ_0003489 decreased IGF2 expression by sponging miR-98-5p and improved paclitaxel sensitivity in resistant NSCLC cells [36]. Lastly, in lung adenocarcinoma, decreased hsa-miR-98 expression in induced pulmosphere cells may indicate a cancer stem cell phenotype [56].
hsa-miR-98-5p suppresses CTR1 gene expression, affecting NSCLC cell cisplatin sensitivity. Moreover, lncRNA NEAT1 sponging hsa-miR-98-5p increased EGCG-induced CTR1 expression and cisplatin sensitivity. This suggests a lung cancer treatment strategy to overcome cisplatin resistance [53]. miR-98 overexpression inhibits epithelial-to-mesenchymal transition (EMT) and metastasis by targeting HMGA2, which represses POSTN, suggesting a therapeutic miR-98-HMGA2-POSTN pathway [53].
hsa-miR-98-5p expression levels in NSCLC patients were associated with a higher objective response rate (ORR) to radiotherapy, suggesting it may be a biomarker [117].
In NSCLC A549 cells, modulating hsa-miR-98-5p with (-)-epigallocatechin-3-gallate (EGCG) and cisplatin increased p53 and cisplatin-induced apoptosis, reducing tumor size and improving drug efficacy [57]. Also, it was found that miR-98 upregulation increased HMGA2 protein levels and increased cisplatin sensitivity in cisplatin-resistant human lung adenocarcinoma cells with a decrease in miR-98 expression [52].
The findings showed notable differences in miR-98 expression between benign pleural effusion (BPE) and lung adenocarcinoma-associated malignant pleural effusion (LA-MPE) samples when properly normalized [118]. Another study suggested using miR-98 and miR-205 expression levels to distinguish normal from cancerous lung squamous cell carcinoma samples [57]. Hsa-miR-98, along with other miRNAs in the hsa-let-7 family, was expressed more in adenocarcinoma (AD) than squamous cell carcinoma (SCC) in transthoracic needle aspiration samples of NSCLC, emphasizing its role in classifying the cancer [58].
miR-98 plays a multifaceted role in lung cancer, acting both as a potential oncogene and tumor suppressor. Numerous studies have revealed its involvement in numerous molecular interactions and pathways that influence lung cancer progression and treatment resistance. Because of MiR-98’s multiple roles, its regulatory mechanisms are critical for lung cancer treatment and biomarker development.
Colorectal cancer (CRC)
Colorectal cancer (CRC) is the third most common type of cancer diagnosed and the second most common cause of cancer-related deaths [59]. MiR-98 expression patterns in the CRC are diverse. While some studies have reported its downregulation, associating it with advanced stages and metastasis, others have found it to be upregulated, especially in early-stage tumors, indicating its potential role in tumor initiation.
Serum miR-98 downregulation is associated with aggressive clinical characteristics and decreased survival in CRC patients, making it a potential prognostic indicator for overall and disease-free survival [60]. This essential understanding lays the foundation for miR-98 regulatory dynamics research in the CRC.
A study found that the long non-coding RNA TMPO-AS1 sponges miR-98-5p to upregulate BCAT1, boosting CRC progression [61]. In a computational investigation, miR-98-5p was found to target FZD3 in the Wnt signaling pathway to decrease CRC tumor proliferation and metastasis. The direct binding of miR-98-5p to the FZD3 mRNA 3’UTR suppressed colorectal cancers [119]. These connections show miR-98’s integrative role in molecular regulatory networks.
Overexpression of miR-98 inhibited the up-regulation of periostin (Postn), which facilitates colon cancer cells in apoptosis and transition from epithelial to mesenchymal [62]. Postn is a let-7a/miR-98 target gene. It has also been demonstrated that boosting miR-98 in CRC cells decreased cell proliferation, migration, and invasion while increasing cell death through decreasing CLDN1 [120].
Understanding CRC molecular features may also require miR-98 expression. Significant downregulation of miR-98-5p in KRAS mutant CRC tissues compared to wild-type was observed, suggesting a molecular signature that could enhance CRC molecular understanding and aid in identifying novel biomarkers [62].
Interestingly, miR-98 directly targeted hexokinase 2 (HK2) to suppress the Warburg effect and reduce glycolysis and proliferation in colon cancer cells [63]. The metabolic regulation of colon cancer cells by miR-98 offers new therapeutic possibilities.
According to P53 status, radiation and SN38 treatments in colon cancer cells modulated miRNA, cytokine, and chemokine expression. miR-98 was highly elevated and associated with colon cancer pathways and cytokine or chemokine expression. This suggested that miR-98 may treat colon cancer, especially in a P53-dependent way [121].
Several miRNAs changed between low- and high-grade intraepithelial dysplastic polyps in a porcine model of familial adenomatous polyposis. miR-98 levels were significantly higher in high-grade polyps, implying a role in colon polyp premalignancy [122]. A study discovered that patients with polyps or adenomas exhibited higher miR-98 expression than controls [123].
Serum levels of miR-92a-3p and miR-98-5p improved chemotherapy response prediction, although not enough to alter therapeutic decisions [63]. It was shown that miR-98-5p, along with clinical and pathological factors, can predict treatment results in metastatic CRC patients receiving first-line systemic therapy [64].
Moreover, in extracellular vesicle (EV) dynamics, investigators unraveled miRNA profiles within three distinct EV subtypes released from the human LIM1863 colon cancer cell line. In shed microvesicles (sMVs), miR-98-5p was selectively represented, depicting a selective enrichment of miR-98-5p in specific EV subtypes [65].
miR-98 plays a multifaceted role in colorectal cancer (CRC) progression and prognosis, with varying expression patterns across different tumor stages and cellular functions. Its involvement spans molecular regulatory networks, affecting CRC cell proliferation, metastasis, apoptosis, and metabolic processes, with potential prognostic and therapeutic implications. Further exploration into miR-98’s intricate interactions and regulatory dynamics in CRC can provide valuable insights for diagnosis, prognosis, and targeted treatments.
Hepatocellular carcinoma (HCC)
Hepatocellular carcinoma ranks as the sixth most common and the fourth deadliest cancer worldwide, predominantly affecting liver cells [124]. In HCC, miR-98 often exhibits decreased expression, and its downregulation has been connected to increased cell proliferation, invasion, and worse overall survival rates in patients.
A critical analysis of miR-98’s function in HCC found that HCC tissues and cell lines had significantly lower miR-98 expression than nearby non-tumorous tissues and the hepatic cell line LO2. It was found that miR-98 decreased HCC cell proliferation by targeting EZH2 and suppressing the Wnt/β-catenin signaling pathway, resulting in a G0/G1 cell cycle arrest [36].
The overexpression of P53 and downregulation of Ang-1 and FGF-1 genes in HepG2 cells showed miR-98’s pro-apoptotic and anti-angiogenic effects [67]. Researchers found that miR-98-5p expression levels in HCC patients’ serum decreased significantly, showing its potential to target and down-regulate the HBEGF gene, affecting disease prognosis when analyzed alongside MRI data [65].
In terms of drug resistance, the lncRNA HEIH regulates miR-98-5p in the PI3K/AKT signaling pathway to mediate Sorafenib resistance in HCC. In HCC cells, suppression of miR-98-5p activates the PI3K/AKT pathway, boosting Sorafenib resistance [125]. Researchers also looked at XLOC_001659/miR-98-5p/MAP3K2, a novel molecular axis that regulates HCC proliferation via submicron silica particles.
MiR-98-5p was significantly downregulated in HCC tissues and cell lines. By targeting IGF2BP1, overexpression of this miR reduced HCC cell growth and promoted apoptosis [68]. MiR-98’s role in macrophage polarization has also been studied, with a focus on its impact on TAM-driven HCC development and invasion [126, 127]. Further studies revealed that miR-98 can downregulate genes such as SALL4 and CTHRC1, reducing HCC cell malignancies and solidifying its function as a tumor suppressor [18, 70].
HBV-related HCC was connected to a distinct miRNA signature in a study on miRNAs. MiR-98 was discovered in HBV-unrelated HCC and HBV infection, implying a greater role in disease pathogenesis. According to Gene Ontology (GO) and KEGG pathway analyses, several miRNAs, including miR-98, impact transcription regulation and MAPK signaling pathway-mediated protein phosphorylation, which is important in HCC and HBV infection [128].
MiR-98-5p downregulation in HBV-HCC tissues and cells increases apoptosis by decreasing NF-B-Inducing Kinase (NIK) expression [71]. Lin-28B overexpression inhibited let-7/miR-98 family members, supporting miR-98’s tumor-suppressive action in HCC, implying that miR-98 downregulation in HBV-HCC may limit tumor proliferation [129].
Researchers discovered that overexpression of miR-98-5p diminished PPP1R15B levels in HaCaT cells, enhancing apoptosis and decreasing cell proliferation. This finding sheds light on how inadequate levels of miR-98-5p in the circulatory system may contribute to diabetes-related skin hyperproliferation [130]. Furthermore, miR-98-5p downregulation was detected in ovarian cancer tissues associated with disease progression, implying that it may also inhibit tumor growth. These findings add to our understanding of the role of miR-98 in cancer and other diseases, such as diabetes [70].
Scientific investigations have highlighted the potential of circulating miRNAs as markers of hepatocarcinogenesis progression in rats. Notably, elevated circulating miR-98 levels were observed even at the early stages of hepatocarcinogenesis [131]. Different studies linked miR-98 to clusters of circulating let-7 family tumor suppressors in chronic hepatitis C patients, suggesting its potential in liver disease monitoring [132]. Another murine model showed miR-98 dysregulation during liver neoplastic processes, suggesting it could be used as a biomarker for early HCC identification and HT1 damage development [71].
Research on the let-7 microRNA family showed miR-98 suppressed Bach1, a known HMOX1 gene repressor, to modulate HMOX1 expression. In human hepatocytes, miR-98 dramatically decreased Bach1 protein levels and increased HMOX1 gene expression, suggesting a way to reduce oxidative injury [72].
In hepatocellular carcinoma (HCC), miR-98 consistently exhibits reduced expression, which correlates with increased cell proliferation, invasion, and poorer patient survival rates. MiR-98 has been linked to several key pathways in HCC, notably inhibiting the Wnt/β-catenin signaling pathway, targeting genes such as EZH2 and IGF2BP1, and impacting drug resistance mechanisms. Moreover, the broad involvement of miR-98 in various other cancers and diseases, such as diabetes and liver disease, underlines its potential as a therapeutic target and diagnostic marker across a spectrum of health conditions.
Prostate cancer (PC)
Prostate cancer is the second most frequent cancer in men and ranks sixth in terms of cancer-related mortality in men worldwide [133]. The expression of miR-98 in prostate cancer (PCa) has been found to be context-dependent. Although certain studies indicate its downregulation, implying a tumor-suppressive role, others show its upregulation in castration-resistant subtypes, suggesting a role in therapeutic resistance.
A comprehensive analysis found significant upregulation of miR-98 and related miRNAs like miR-152-3p, miR-326, and miR-4289 in the plasma of PCa patients compared to healthy subjects, showcasing high diagnostic precision with an AUC of 0.88. Downregulation of these miRNAs was often linked with advanced cancer stages and unfavorable survival outcomes, suggesting potential diagnostic and prognostic relevance specific to PCa [134].
It was discovered that the long non-coding RNA, NEAT1, acts as a sponge for miR-98-5p, thus promoting the expression of the oncogene HMGA2 in PCa. With NEAT1 being notably up-regulated in PCa tissues and cell lines and its reduction halting the growth and invasion of certain cells, this sheds light on a crucial mechanism in PCa development and progression [73].
There’s evidence suggesting miR-98 could be modulated by vitamin D administration. One study demonstrated that 1,25-VD transcriptionally induces miR-98, subsequently inhibiting specific cell growth and leading to the reduction of CCNJ, a particular mitotic control protein. This emphasizes the potential therapeutic role of vitamin D in PCa via miR-98 modulation [72].
Supporting these findings, another research found a significant increase in levels of miR-98-5p and other miRNAs in the plasma of PCa patients, confirming the diagnostic potential. Further, specific miRNAs, such as miR-152-3p, have been associated with increased PCa cell proliferation and migration, underscoring their vital role in PCa progression [73].
A meta-analysis aimed at identifying co-deregulated miRNA genes highlighted a series of upregulated miRNAs, including miR-98, in recurrent PCa post-radical prostatectomy. These miRNAs were implicated in pivotal pathways regulating various cellular processes and modulating several significant proteins, illustrating a broad molecular interaction [135].
Another significant contribution was the development of a diagnostic model using plasma miRNAs. The study identified miR-98-5p and miR-26b-5p as potential molecular markers for distinguishing PCa cases, especially differentiating low-grade from high-grade prostate cancer [136].
Diving deeper into the intricate patterns of miRNA, a study explored the interaction between testosterone, dietary tomato carotenoids, and miRNA expression during the early phases of prostate carcinogenesis. It was concluded that diet can modulate specific miRNAs like miR-98, revealing new insights into dietary influences on prostate carcinogenesis [75].
Lastly, an investigation of six microRNAs, including miR-98 revealed a decreased expression of miR-98 in PCa patients compared to benign prostatic hyperplasia (BPH) cases. This reduced expression correlated with the Gleason grades of PCa, reinforcing the significance of miR-98 as a valuable biomarker for PCa detection and prognosis [74].
In prostate cancer (PCa), miR-98’s expression is complex and varied, with research indicating both tumor-suppressive and resistance-associated roles. Significant studies have shown miR-98’s diagnostic precision in differentiating PCa patients from healthy subjects and its association with key pathways and oncogenes, such as the oncogene HMGA2 via the lncRNA NEAT1. Additionally, the potential modulation of miR-98 by factors like vitamin D and dietary tomato carotenoids emphasizes its multifaceted role in prostate cancer development, progression, and potential therapeutic interventions.
Pancreatic ductal adenocarcinoma (PDAC)
The incidence of PDAC, a highly aggressive disease that affects people all over the world, has increased recently [137]. The importance of MiR-98 in pancreatic ductal adenocarcinoma has been highlighted by studies revealing its role in tumor progression and treatment resistance.
In a study on pancreatic adenocarcinoma (PAAD), a connection between glycolysis and the LINC02432/hsa-miR-98-5p/HK2 molecular triad was identified. A higher hallmark glycolysis score, derived from the single-sample GSEA (ssGSEA) algorithm, was linked to a poorer prognosis for PAAD patients. An analysis from the TCGA and GEO databases revealed the LINC02432/hsa-miR-98-5p/HK2 axis, which was found to be inversely related to ferroptosis. A higher ceRNA risk score was correlated with increased M0 macrophage infiltration in PAAD, associations with specific chemokines, the immune checkpoint gene SIGLEC15, and a positive relationship with the tumor mutation burden (TMB). Patients with elevated risk scores showed better responsiveness to drugs targeting EGFR, MEK, and ERK [138].
In another investigation, it was observed that miR-98-5p was significantly downregulated in PDAC tissues, influencing vital clinical outcomes. This downregulation affected PDAC cell behavior, promoting proliferation and migration. Through assays, MAP4K4 was pinpointed as a direct target of miR-98-5p. The overexpression of miR-98-5p suppressed the MAPK/ERK signaling pathway, primarily by downregulating MAP4K4, suggesting its therapeutic potential in PDAC [32].
Although the downregulation of miR-98 in PDAC suggests that it plays an important role in disease progression and has therapeutic potential, more research into miR-98’s role in PDAC is needed to fully understand its behavior.
Gastric cancer (GC)
Currently the second greatest cause of death globally, gastric cancer has emerged as one of the most common cancers [76]. MiR-98 expression has been identified as a critical determinant in gastric adenocarcinomas, with altered levels correlating with tumor progression, metastasis, and treatment responses.
The overexpression of the long noncoding RNA PITPNA-AS1 in GC correlates with poorer survival rates. This lncRNA directly interacts with miR-98-5p, inhibiting it and thereby leading to cisplatin treatment resistance in GC cells. Conversely, suppression of PITPNA-AS1 curtailed cell growth and increased cisplatin sensitivity [77]. There’s also evidence that downregulation of miR-98-5p in CD44 + GC stem cells results in increased cancer cell stemness and chemoresistance by targeting BCAT1. However, miR-98 overexpression could reverse such effects [77]. Additionally, miR-98-5p downregulation in GC tissues saw an upregulation in Treg/Th17-related factors. Overexpressing miR-98-5p can regulate this balance by targeting IL-6, with the balance being further modifiable by oleanolic acid through miR-98-5p upregulation, hinting at a treatment pathway for GC [78]. Furthermore, a ceRNA network linked to Pepsinogen C (PGC) expression in GC involving miR-98-5p was identified, showcasing a complex interplay between lncRNAs, circRNAs, and miRNAs in modulating PGC expression and influencing GC progression post-transcriptionally [79]. Another layer of complexity emerges with the interaction between lncRNA TTTY15 and miR-98-5p. Silencing TTTY15 slows GC progression by acting on miR-98-5p and downregulating cyclin D2 (CCND2) expression, as corroborated by increased TTTY15 and CCND2 expression, and decreased miR-98-5p in GC tissues and cell lines [78].
Studies into miRNA and mRNA signatures in hydroxycamptothecin (HCPT)-resistant GC cell lines identified 25 miRNAs, including miR-98, deregulated in HCPT-resistant cells, impacting cancer development, progression, and chemosensitivity [139]. Similarly, a noteworthy up-regulation of 22 out of 24 miRNAs, inclusive of miR-98, was found in GC compared to normal gastric tissue, suggesting a significant role in GC progression [79].
The intricate molecular interaction of MiR-98 in gastric cancer indicates its potential as a diagnostic and therapeutic tool. Given its complex interactions and effects, there is an urgent need for comprehensive research to determine its precise role and potential applications in gastric cancer management.
Ovarian cancer (OC)
The seventh most common malignant tumor in women worldwide is ovarian cancer. About 239,000 cases of OC are reported annually, and 152,000 deaths have been attributed to the condition [80]. MiR-98 has emerged as a significant factor in ovarian cancer, with its expression levels influencing various oncogenic pathways and patient outcomes.
It was found that miR-98-5p is enriched in cisplatin-resistant epithelial ovarian cancer (EOC) cells, promoting cisplatin resistance by hindering miR-152 biogenesis through targeting Dicer1, which is correlated with poor outcomes in EOC patients [81]. Contrarily, it was shown that miR-98-5p is downregulated in ovarian cancer tissues, and its mitigative effects on cancer are hampered by overexpressed lncRNA DSCR8, which is known to promote cancer progression through a highlighted lncRNA DSCR8/miR-98-5p/STAT3/HIF-1α axis [70]. A mechanism was highlighted in which cancer-associated fibroblast-derived exosomal miR-98-5p promotes cisplatin resistance by downregulating CDKN1A [82]. Networks involving miR-98-5p, associating it with tumorigenesis, progression, and chemoresistance in ovarian serous cystadenocarcinoma and carboplatin-resistant ovarian cancer, were explored [81, 140]. It was demonstrated that miR-98, alongside let-7, targets and regulates PGRMC1 expression, a component known to be tied to chemoresistance, suggesting a regulatory mechanism for PGRMC1 expression in ovarian cancer [95]. Among a panel of miRNAs, miR-98-5p was identified as a biomarker for resistance to platinum-based chemotherapy in high-grade serous ovarian cancer (HGSC) [82].
On a broader scale, miR-98 was recognized as significantly associated with survival in ovarian cancer patients, indicating a potential role in improving treatment decisions. While focusing on endometrial transition, aberrant expression of miR-98 was associated with the transition into cancerous states, with miR-98 being observed to have an inverse relationship with PGRMC1 and PGR expression [97]. A contrasting scenario was revealed where the knockdown of SNHG4, known to reduce ovarian cancer cell malignancy, was reversed by miR-98-5p downregulation or TMED5 overexpression [83].
The diverse roles of miR-98-5p in ovarian cancer, from influencing disease progression to chemoresistance, underscore its potential as a valuable biomarker. Given its diverse impacts, there is a pressing need for deeper research to optimize its application in therapeutic approaches for ovarian cancer.
Bladder cancer
Bladder cancer is a significant global health challenge and ranks among the top ten most common cancer types worldwide [84]. Bladder carcinoma research has consistently shown the critical role of miR-98, with its downregulation impacting tumor growth and response to chemotherapy.
Various molecular interactions involving miR-98-5p or miR-98 that contribute to the progression and malignancy of bladder cancer through different axes and regulatory loops are explored. A feedback loop involving TMPO-AS1/miR-98-5p/EBF1, which significantly impacts the development of bladder cancer, was demonstrated; in this loop, TMPO-AS1 is sponged by miR-98-5p, which subsequently targets EBF1 [85]. An upregulation of LINC00885 targeting the miR-98-5p/PBX3 axis, promoting bladder cancer progression, was elucidated; here, an upregulation of miR-98-5p is observed to reduce cell proliferation and enhance cell apoptosis [86]. The upregulation of miR-98 in bladder urothelial carcinoma tissues and cell lines, promoting proliferation and drug resistance while reducing apoptosis in bladder cancer cells, was highlighted; specifically, LASS2 is targeted by miR-98, and mitochondrial function is regulated, affecting chemoresistance [87]. Lastly, the upregulation of SNHG16 in bladder cancer was revealed; it negatively regulates miR-98 expression, which contributes to bladder cancer malignancy through the miR-98/STAT3/Wnt/β-catenin pathway axis. This showcases a complex regulatory interaction between SNHG16, miR-98, and STAT3, influencing the Wnt/β-catenin pathway and bladder cancer development [87].
The different interactions and regulatory loops involving miR-98 in bladder cancer progression highlight its potential significance as both a therapeutic target and a diagnostic biomarker. Understanding these complex networks can offer promising avenues for enhancing bladder cancer treatment and diagnosis.
Leukemia
Leukemia involves the rapid growth of abnormal white blood cells, with types like acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) impacting adults differently [84]. In hematological malignancies like leukemia, the role of miR-98 is intricate. For instance, in chronic lymphocytic leukemia, miR-98 appears to be downregulated and is linked with disease progression. In contrast, in certain subtypes of acute myeloid leukemia, miR-98 is found to be upregulated, potentially playing a role in the inhibition of cell differentiation.
Investigators provided insights into the role of miR-98 and other microRNAs in different types of leukemia and their implications in treatment and prognosis. A significant reduction in the expression of miR-32-5p, miR-98-5p, and miR-374b-5p in Chronic Lymphocytic Leukemia (CLL) patients was observed, suggesting these miRNAs might act protectively against CLL progression [141]. miR-98 was found to be downregulated in the leukemia drug-resistant cell line K562/A02, and its upregulation was shown to reduce leukemia cell proliferation and enhance chemosensitivity by inhibiting E2F1 expression, highlighting the potential of miR-98 in overcoming leukemia multidrug resistance [89]. High miR-98 expression in acute myeloid leukemia (AML) patients undergoing chemotherapy was reported to be associated with longer survival outcomes, implying its prognostic value [142]. The potential utility of miR-98, among others, in classifying cellular or molecular subgroups of childhood acute leukemias (AL) was underscored, although specific expression details or regulatory impacts in AL were not provided [88].
The various roles of miR-98 across leukemia subtypes highlight its potential as a therapeutic and prognostic tool, emphasizing the importance of further research into its diverse interactions within hematological malignancies.
Thyroid cancer (TC)
A significant portion of endocrine system tumors are thyroid cancers [89]. In thyroid carcinomas, particularly in papillary thyroid cancer (PTC), miR-98 is often downregulated. This reduction in miR-98 levels has been associated with more aggressive tumor phenotypes, lymph node metastasis, and a poorer prognosis. Additionally, miR-98 seems to modulate the resistance to radioiodine therapy in advanced stages.
Researchers examined the roles and interactions of miR-98 in papillary thyroid cancer (PTC) progression, its molecular regulation, and potential racial disparities in its expression. The regulatory mechanism wherein the lncRNA OIP5-AS1 is targeted by miR-98, subsequently activating ADAMTS8 and influencing PTC cell progression, was highlighted [90]. In papillary thyroid carcinoma, a reduced miR-98-5p level was detailed to correspond with elevated HMGA2 expression, which subsequently affects cell growth and apoptosis, emphasizing the regulatory role of miR-98-5p on HMGA2 [143]. Racial variations in miR-98 expression among PTC patients were spotlighted, with downregulation noted in tumor tissues compared to normal ones, suggesting potential racial implications in PTC prognosis and hinting at the possibility of tailored treatment strategies based on these differential miRNA expressions [144].
The studies emphasize the critical role of miR-98 in influencing thyroid cancer dynamics, highlighting not only its therapeutic and prognostic potential but also the importance of considering racial disparities in its expression and subsequent treatment implications.
Cervical cancer (CC)
Cervical cancer is the fourth most common malignant tumor in women and the primary cause of death from reproductive tumors worldwide [145]. In cervical cancer, predominantly triggered by the human papillomavirus (HPV), there is a notable decrease in miR-98 expression, a microRNA with implications for cell proliferation, invasion, and apoptosis.
A downregulation of miR-98-5p in CC tissues and cell lines was discerned, with its overexpression found to inhibit cell proliferation, invasion, migration, and EMT while promoting apoptosis. Notably, the overexpression of miR-98-5p was also observed to suppress the PI3K/Akt pathway in CC [90]. The significance of understanding genetic and epigenetic mechanisms in carcinogenesis, especially for cancer drug design, was underscored. In HeLa cells, a model for CC, it was highlighted that miR-98’s dysregulation (though unspecified as up or downregulated) could induce cell proliferation and anti-apoptosis through pathways like NFκB, TGF-β, and PI3K [93]. The role of miRNAs, including miR-98, in influencing drug resistance was emphasized, particularly in the case of docetaxel, even though the specific cancer type wasn’t provided [110]. High pre-miR-98 levels across various cell lines, irrespective of malignancy or LIN28B expression, were reported, but its specific role in CC was not detailed. Has-miR-98-5p was identified as a potential but under-researched microRNA regulator in HPV oncogenesis, mainly linked to cervical and other cancers, without specifying its exact functions [146].
The studies emphasize the role of miR-98-5p in cervical cancer development and its influence on essential cellular pathways. Furthermore, the potential of miR-98 in determining drug sensitivity and its relevance in HPV-related oncogenesis, especially in cervical cancer, are highlighted, warranting more detailed investigations.
Head and Neck squamous cell carcinoma (HNSCC)
Head and Neck Squamous Cell Carcinoma (HNSCC) is recognized as the seventh most common type of cancer globally, comprising a diverse group of tumors in the upper aerodigestive tract, with squamous cell carcinoma being the most prevalent histology [92]. In HNSCC, miR-98 is often downregulated and is associated with tumor size, stage, and nodal metastasis. Notably, it has been implicated in mediating resistance to radiation therapy in these cancers.
In the realm of HNSCC, miR-98 has been shown to play an important role in cancer progression and potential therapeutic pathways.
A significant decrease in miR-98 expression in squamous cell carcinoma of the head and neck (SCCHN) was observed, with its downregulation being linked to advanced clinical stages, lymph node metastasis, and shorter survival rates. Such downregulation was found to promote malignant activities like cell proliferation, migration, and invasion through the targeting of MTDH, an oncogene [94]. In osteosarcoma, interactions between miR-98-5p and the long noncoding RNA (lncRNA) SNHG16 were revealed, influencing cell proliferation, migration, and invasion [78]. Similar interactions were observed in oral squamous cell carcinoma (OSCC) between miR-98-5p and the lncRNA HOXA11-AS [93, 147]. NiU et al. found that HOXA11-AS stimulates the progression of OSCC via sponging miR-98-5p to upregulate the expression of YBX2 [93]. A panel of miRNA deregulations, inclusive of miR-98, was highlighted in HNSCC, suggesting a potential significance of miRNA in head and neck/oral cancer progression, though specific findings about miR-98 were not detailed [148]. In laryngeal squamous cell carcinoma (LSCC), a notable reduction of miR-98 was documented. The overexpression of miR-98 in this context was found to reverse epithelial-to-mesenchymal transition (EMT) and inhibit metastasis by targeting HMGA2 []. The regulatory impact of miR-98 on HMGA2 expression in HNSCC under hypoxic conditions was recognized, correlating with increased chemoresistance to drugs like doxorubicin and cisplatin [149].
The diverse interactions of miR-98 with various oncogenes and long noncoding RNAs in HNSCC indicate its significant regulatory role in disease progression and treatment outcomes. This emphasizes the importance of further exploring miR-98’s potential as both a therapeutic target and a key player in understanding HNSCC pathogenesis.
Renal cell carcinoma (RCC)
Renal cell adenocarcinoma is one of the ten most common cancers worldwide, accounting for 85% of patients with primary renal neoplasms. The mortality rate of RCC has increased to 40% due to its significant increase in frequency [150]. In RCC, the most common form of kidney cancer, miR-98 dysregulation varies among subtypes. While it’s downregulated in clear cell RCC, pointing towards a tumor-suppressive role, in chromophobe RCC, it appears to be upregulated, suggesting context-dependent functions.
The potential of the dendritic cell vaccine DC-Ad-GM·CAIX in RCC treatment was investigated, with the therapy’s safety and effectiveness observed in Balb/c mouse models. However, tumors that evaded this immunotherapy were found to display altered immunoediting mechanisms, with differential gene expression and therapy evasion miRNAs, including miR-98. The specifics of miR-98’s regulation were not detailed [151]. In a study on clear cell renal cell carcinoma (ccRCC) subtypes, miR-98 was identified as part of a set of miRNAs in competing gene pairs with a notable accuracy of over 92% in predicting ccRCC subtypes. Yet the exact regulatory status of miR-98 remained unspecified [152].
Osteosarcoma (OS)
Osteosarcoma, an infrequent type of bone cancer, occurs at a rate of about 3.4 cases per million people each year worldwide, predominantly affecting children and teenagers [153]. In osteosarcoma, a primary bone malignancy, miR-98 is commonly downregulated. This decreased expression promotes cell growth, migration, and invasion. Moreover, miR-98 has been studied for its role in mediating chemotherapy resistance, particularly to drugs like cisplatin.
In the context of osteosarcoma, the involvement of lncRNA SNHG16, which is believed to act as a molecular sponge for miR-98-5p in modulating different cellular activities, has been unveiled. It has been elucidated that the effects provoked by the knockdown of SNHG16 can be countered by inhibiting miR-98-5p, underscoring a significant interplay [154]. In another observation, miR-98-5p was presented as a pivotal hub in the miRNA-mRNA network, suggesting its essential importance in the molecular matrix of osteosarcoma. Through extensive network analysis, the potential of miR-98-5p and other miRNAs as likely therapeutic targets or biomarkers has been proposed, emphasizing their potential impact on diagnostic or treatment strategies for osteosarcoma [39].
Endometrial cancer (EC)
Endometrial cancer ranks as the sixth most common cancer among women worldwide [155]. MiR-98’s role in endometrial carcinomas, especially in its early stages, has garnered attention. Reduced expression of miR-98 has been correlated with deep myometrial invasion and lymphatic metastasis, hinting at its role in tumor progression.
Transitioning to endometrial cancer, miR-98 has been depicted as a tumor suppressor. Specifically, the role of miR-98 in mediating paclitaxel resistance by attenuating the expression of MRP-7 (Multidrug Resistance Protein 7) was demonstrated. A linkage between the downregulation of miR-98 and augmented MRP-7 levels was established, thereby promoting paclitaxel resistance and enhanced cellular invasiveness in EC [94]. Conversely, the changing expressions of miR-98 during the evolution from normal to cancerous states in endometrial tissues were explored, showing an inverse relationship between miR-98 and PGRMC1 (Progesterone Receptor Membrane Component 1). Notably, an overexpression of miR-98 was found to lead to repression of PGRMC1 and CYP19A1 genes, subsequently resulting in decreased cell proliferation rates in EC cells [].
Melanomas
Melanoma, the most lethal type of skin cancer, has been on the rise throughout the past thirty years and is the leading cause of skin cancer-related deaths worldwide [156]. It affects both male and female patients, ranking fifth and sixth among all human tumors based on current epidemiological investigations [157]. In cutaneous melanomas, miR-98 appears to have an intricate role. Elevated levels of miR-98 have been associated with the early stages of melanoma but are often reduced in the advanced, metastatic stages. This suggests that its role might shift from being potentially oncogenic in the early stages to tumor-suppressive in the later stages.
In studies of melanoma, a decline in miR-98 expression was found to be correlated with progressing tumor stages and escalating metastasis. Through these investigations, the inhibitory effects of miR-98 on melanoma cell migration and metastatic tumor size were revealed, orchestrated through a newly discovered miR-98-IL-6-negative feedback loop. This interplay between miR-98 and IL-6 via the Stat3-NF-κB-lin28B pathway is indicative of a complex regulatory mechanism influencing melanoma progression [96].
Glioblastoma Multiforme (GBM)
In glioblastoma multiforme, one of the most aggressive brain tumors, miR-98 has been found to be downregulated. This decrease in miR-98 levels correlates with enhanced cellular proliferation, migration, and angiogenesis. Some studies also indicate its role in mediating temozolomide resistance in GBM.
In GBM, the diagnostic and therapeutic potential of miR-98 was emphasized. A set of serum exosomal miRNAs, including miR-98-5p, was highlighted as potential diagnostic biomarkers due to their differential expression compared to normal controls. These miRNAs were found to be related to cell proliferation and signaling pathways in GBM, impacting prognosis [158]. On the other hand, the downregulation of miR-98 in glioma tissues was shown, revealing its crucial role in managing glioma cell migration and invasion. When miR-98 was re-expressed, the invasive potential of glioma cells was reduced. The targeting of the transcription factor pre-B-cell leukemia homeobox 3 (PBX3) by miR-98 further emphasized its importance in controlling GBM invasion, suggesting that the overexpression of miR-98 might be a potential therapeutic strategy to modulate PBX3 [97].
miR-98 in cancer diagnosis and prognosis
MiR-98 has emerged as a significant player in the landscape of cancer diagnosis and prognosis, playing multiple functions across various cancer types. For instance, high expression of miR-98 has been identified as a positive prognostic factor in acute myeloid leukemia patients undergoing chemotherapy, indicating its potential as a therapeutic target [159]. In breast cancer, miR-98 can inhibit angiogenesis and invasion, primarily by suppressing the expression of ALK4 and MMP11, emphasizing its potential utility in prognosis and treatment approaches [159].
Moreover, circulating miR-98, as detected in serum, exhibits promise as a biomarker for both diagnosis and prognosis in colorectal cancer, although further clarification is warranted to fully understand its clinical significance [60]. In non-small cell lung cancer (NSCLC), a reduction in serum miR-98 levels correlates with an unfavorable prognosis, suggesting its prognostic merit. Additionally, miR-98’s expression level has an inverse relationship with the TWIST mRNA level in NSCLC, providing novel potential for understanding and fighting this malignancy [47, 55].
The investigative route to the function of miR-98 extends to its capability of inhibiting tumor angiogenesis and invasion by targeting specific genes like activin receptor-like kinase-4 and matrix metalloproteinase-11, which further broadens our understanding of its anti-cancer attributes [159]. As scientific research explores further into the molecular complexity of miR-98, the potential for innovative diagnostic and prognostic tools, as well as therapeutic strategies, continues to unfold.
Therapeutic strategies for modulating miR-98 expression in cancer cells
Modulating miR-98 expression in cancer cells demonstrates a variety of therapeutic strategies, given its established role in cancer progression and metastasis. For instance, a study indicated that the CCL18-mediated down-regulation of miR-98 enhanced epithelial-to-mesenchymal transition (EMT) in breast cancer cells, promoting metastasis. This modulation was explored in hepatocellular carcinoma-conditioned tumor-associated macrophages, exhibiting the potential of miR-98 mimics in treatment [127]. MiR-98 displayed the potential to reduce resistance to cisplatin therapy, suggesting a therapeutic benefit in enhancing chemosensitivity [94].
Further, silencing miR-98 expression has been observed to induce cell proliferation, migration, and invasion in nasopharyngeal carcinoma (NPC) cells, both in vitro and in vivo, indicating a potential strategy of miR-98 inhibition for preventing cancer progression [160]. In the case of gastric cancer, lentivirus-mediated miR-98 overexpression in gastric cancer stem cells (GCSCs) showed a potential therapeutic path, reflecting the miRNA’s impact on cancer cell stemness. Moreover, miR-98-mediated macrophage polarization in the progression of hepatocellular carcinoma provides another aspect of therapeutic modulation, broadening the scope of miR-98’s influence on the tumor microenvironment and subsequent therapeutic interventions [127].
These insights collectively demonstrate a diverse landscape of therapeutic strategies centered on miR-98 modulation, ranging from enhancing chemosensitivity to modulating cancer cell behaviors and interacting with the tumor microenvironment, all of which offer significant promise for advancing cancer treatment approaches.
Conclusions
The exploration of miR-98’s role in cancer biology has revealed its potential as an important modulator of tumoral and microenvironmental behavior. MiR-98 has been implicated in various aspects of cancer progression, including cell proliferation, migration, and invasion, as well as chemoresistance and macrophage polarization [94, 127, 160, 161]. However, the way to understanding miR-98’s full therapeutic potential involves dealing with challenges and depends on a thorough understanding of its molecular and cellular interactions.
One significant challenge resides in the complex nature of miR-98’s molecular pathways. Its interaction with diverse molecular targets such as ALK4, MMP11, and STAT3 points out a complex network of regulatory mechanisms that may exhibit variable behaviors across different cancer types and stages [159, 160]. The impact of miR-98 modulation on the tumor microenvironment, particularly its role in macrophage polarization, further compounds the complexity and necessitates a nuanced approach to therapeutic strategy development [127].
Moreover, the delivery and stability of miR-98 modulating agents present another layer of challenge. Effective delivery systems that ensure targeted and sustained miR-98 modulation while minimizing off-target effects are imperative for translating preclinical findings into clinical success. Additionally, the potential for acquired resistance to miR-98-based therapies, similar to other molecularly targeted therapies, requires thorough investigation.
In the future, an integrated approach encompassing robust preclinical models, advanced delivery systems, and comprehensive molecular studies is vital. Uncovering the broader spectrum of miR-98’s interactions within the cancerous environment and its crosstalk with other regulatory molecules and pathways will be essential in developing effective therapeutic strategies. Additionally, multi-centric clinical trials evaluating the safety, efficacy, and optimal delivery methods for miR-98 modulating agents are crucial for advancing this therapeutic frontier.
Interdisciplinary collaborations among molecular biologists, oncologists, and nanotechnology researchers could also foster innovative approaches to the issues at hand. The merging of insights from molecular studies, clinical observations, and nano-delivery platforms may pave the way towards utilizing miR-98’s therapeutic promise in cancer treatment, announcing a new era of targeted molecular therapies.
In conclusion, miR-98 holds substantial promise as a candidate for cancer therapeutics. Overcoming the outlined challenges and relying on future opportunities could significantly accelerate the way toward effective miR-98-based cancer therapeutic strategies.
Data availability
No datasets were generated or analysed during the current study.
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V.H. contributed to conceptualization, review, and editing. S.A. contributed to figure preparation, review, and editing. P. I. contributed to the review and editing. H.M. contributed to preparing the table and editing. F.S. and Z. R. contributed to the conceptualization, writing the original draft, review, and editing. All authors read and approved the final manuscript.
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Hazari, V., Samali, S.A., Izadpanahi, P. et al. MicroRNA-98: the multifaceted regulator in human cancer progression and therapy. Cancer Cell Int 24, 209 (2024). https://doi.org/10.1186/s12935-024-03386-2
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DOI: https://doi.org/10.1186/s12935-024-03386-2