Introduction

Tyrosine Kinases(TK) consists of 90 enzymes whose main function is to catalyze the transfer of ATP phosphate groups to tyrosine residues of target proteins [1]. According to their structures, they can be divided into receptor protein tyrosine kinases (RTKs) and non-receptor protein tyrosine kinases (NRPTKs). RTKs include EGF receptor family, MET receptor family, ALK receptor family, FGF receptor family, RET receptor family, VEGF receptor family, Eph receptor family and DDR family etc. NRPTKs include SRC family, SYK family, FES family, FAK family, ABL1 and BCR-ABL family, and JAK family etc. The substrates are phosphorylated as a signaling mechanism between the cell surface, cytoplasmic proteins, and nuclear activation [2]. When cells are exposed to external and internal stimuli, TKs participate in cell proliferation, survival, differentiation, and metabolism [3, 4].

The SRC family of kinases (SFKs) is one of the overexpressed TKs in cancers. Previous studies identified eight SRC family kinases (SFKs) in Homo species, and several of these genes play crucial roles in cancer progression. The Oncomine platform contained 448 unique analyses for FYN expression, which was overexpressed in 8 of 448 unique analyses. SRC had significant expression in 8 of 409 unique analyses, YES had significant expression in 14 of 460 unique analyses, LCK had significant expression in 14 of 466 unique analyses, LYN had significant expression in 33 of 459 unique analyses, HCK had significant expression in 18 of 432 unique analyses, FGR had significant expression in 14 of 452 unique analyses, and BLK had significant expression in 8 of 429 unique analyses (Fig. 1).They have been proposed as molecular targets for treatment for decades [5]. FYN, also known as p59-FYN, SLK, SYN, is a 59 kDa protein containing 537 amino acids with genetic information located on chromosome 6q21 and was originally identified as a member of the SFKs [6]. FYN is primarily localized to cytoplasmic leaflets in the cytoplasmic membrane, which phosphorylates tyrosine residues of the key molecules involved in different signaling pathways [7]. FYN is a tyrosine kinase involved in transporting various cell surface receptors from the cytoplasmic signaling cascade. FYN contains the N-terminal region required for plasma membrane binding, and two Src homology (SH) domains (SH2 and SH3) are involved in protein interactions and are highly conserved catalytic domains, including the adenosine triphosphate (ATP) binding site and the C-terminal tail, which contains a negative regulatory tyrosine site phosphorylation [8]. In between the SH2 and SH1 structural domain is a circular SH2-linked mediator with a pseudo-SH3 binding site containing a tyrosine residue (Y416), which is activated by autophosphorylation and is required for its optimal activity [9, 10]. The active site of the kinase is in the SH1 structural domain, followed by the C-terminal regulatory fragment. Dephosphorylation of tyrosine residue (Y527) activates SKFs because it exposes the SH1 region tyrosine site, which can be modified by phosphorylation [11]. FYN regulates cell growth, survival, adhesion, cytoskeletal remodeling, motility, axon guidance, synaptic function, and central myelin-forming nervous system, in addition to platelet activation and T-cell receptor signaling [12,13,14,15,16,17].

Fig. 1
figure 1

The mRNA expression levels of the SRC family in human cancers. The number of analyses that meet the thresholds was shown in the colored cells. The gene rank determines the cell color, which represents the importance of genes in cancer. The red and blue indicate over-expressed and under-expressed respectively, and the brighter red or blue implies a gene with a higher or lower level of expression that is more statistically significant

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Regulatory mechanisms of FYN expression and activity

 Protein levels significantly impact protein kinase activity, which in turn greatly influences the biological significance of protein kinases. Thus, the main factors affecting FYN expression in cancer are transcription factors, miRNA, and ubiquitinated degradation (Fig. 2)

Fig. 2
figure 2

Major factors regulating FYN mRNA and protein expression. The main factors affecting FYN expression in cancer are transcription factors, miRNA, and ubiquitin E3 ligases

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Transcription factors

During chronic myeloid lymphocytic leukemia (CML), the transcription factors SP1 and EGR1 bind to the FYN promoter, which reduces FYN expression [18]. FYN expression levels and downstream protein activation are decreased in pancreatic cancer cells where transcription factor PRDM14 is knocked down [19]. High levels of FYN and STAT5 are present in the positive feedback loop between basal breast cancer cells. FYN interacts directly with STAT5 and increases p-STAT5, which further acts as a transcription factor for FYN [20]. In Acute lymphoblastic leukemias, FYN is a target gene for the transcription factor RUNX2 [21]. Additionally, KLF5 binds to the FYN promoter region to induce its transcription, and overexpression of FYN improves lamellar pseudopod formation and migration in bladder cancer cells in which expression of KLF5 is reduced [22].

MicroRNA (miRNA)

It has been demonstrated that miR-125a-3p regulates FYN expression and contributes to the progression of multiple cancers [23,24,25,26,27,28]. FYN is a downstream target of miR-153-3p, and the downregulation of miR-153-3p levels promotes FYN expression for esophageal squamous cell carcinoma (ESCC) proliferation [29]. The miR-381 inhibits MAPK signaling by downregulating FYN, thereby making breast cancer cells more sensitive to doxorubicin (DOX) [30]. miR-369 also has been demonstrated to target the 3’UTR of FYN to regulate its expression [31]. Several proteins in the megakaryocyte GPVI signaling pathway, including FYN, are regulated by miR-15a-5p [32]. miR-140 inhibits FYN kinase mRNA to establish axon-dendritic polarity [33]. FYN is regulated by miR-431-5p in diffuse large B-cell lymphoma (DLBCL) [34]. Bioinformatic analysis revealed that FYN is a target gene of miR-122-5p[35]. miR-466 overexpression significantly reduces the expression of a network of transcription factor RUNX2 target genes, including FYN, and inhibits tumor growth and bone metastasis in prostate cancer [36]. A systematic analysis of miRNA-mediated gene regulation in tamoxifen-resistant breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive cell lines demonstrated that miR-33b, miR-342-5p were significantly associated with FYN and can directly regulate its expression [37]. FYN can also promote the biosynthesis of miR-5088-5p by inducing its hypermethylation to mediate breast cancer proliferation and metastasis [38]. In the current study, several miRNAs were identified that could regulate FYN expression-mediated role in cancer. More miRNAs associated with FYN expression will likely be discovered in the future.

Degradation of post-translational ubiquitination

It has been demonstrated that endogenous Cbl mediates the ubiquitination of FYN and determines the rate of FYN protein turnover [39, 40].

The upstream regulators of FYN

The upstream regulators of FYN

The function of FYN as a protein kinase in cancer is regulated by protein levels and its activity, and this section will focus on its upstream regulatory molecules (Fig. 3).

Fig. 3
figure 3

An overview of FYN-interacting proteins. Multiple molecules can regulate FYN activation or inactivation through phosphorylation, and once activated, FYN interacts with and phosphorylates a wide variety of proteins serving as mitotic regulators, oncogenes or tumor suppressors

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By activating FYN, Integrin beta6 can trigger the Raf-ERK/MAPK pathway to promote the progression of oral cancer [41]. SHP2 facilitates the localization and activation of FYN downstream of alpha6beta4 integrin to promote cancer invasion [42]. According to Akash Gulyani and colleagues, adhesion/integrin signaling influences cellular FYN activity [43]. Expressing constitutively active EGFR mutant EGFRvIII results in FYN phosphorylation, which promotes glioblastoma progression and invasion [44]. In breast cancer, the Ras oncogene significantly upregulates FYN mRNA, protein, and kinase activity [45]. The binding of platelet-derived growth factor (PDGF) to its receptor leads to activation of the protein tyrosine kinase FYN, which is phosphorylated on the N-terminal portion of Tyr28 after interacting with the intracellular structural domain of the PDGF β receptor. Subsequently, it is autophosphorylated on Tyr30, Tyr39 and Tyr420 [46]. It has been displayed that FYN is phosphorylated by PKA on S21. This phosphorylation regulates FYN activity, adherent spot targeting and is required for cell migration, and mutating S21 to S21A blocks PKA-mediated FYN phosphorylation and alters its tyrosine kinase activity [47]. Kinome analysis of human natural killer cell receptor-induced phosphorylation revealed that triggering CD16 resulted in phosphorylation of FYN at N-terminal S21, S25, and S26, while adjacent Y28 depicted a trend towards dephosphorylation [48]. In the FYN/ Vav1 complex, FYN can be phosphorylated at the Tyr-129 [49, 50]. FYN kinase activity is inhibited by PTPa knockdown, and elevated FYN activity in the presence of PTPa results from increased phosphorylation of FYN at Tyr-528 and Tyr-417 [51]. CD5 activation induced tyrosine phosphorylation of FYN and inhibited phosphorylation of ZAP-70, and FYN activity was inhibited by phosphorylating its inhibitory C-terminal Tyr531 [52]. IEC18 cells transfected with K-ras have increased phosphorylation of FYN on Tyr-142 and elevated kinase activity than controls [53]. SHP2 knockout cells demonstrated increased phosphorylation and reduced kinase activity at the inhibitory pY531 of FYN [54]. LL-37 and IG-19 inhibit IL-32/FYN kinase activity by inhibiting the Y420 of FYN phosphorylation mediated by interleukin-32 (IL-32) [55]. CD5-FYN phosphorylation is maintained at equilibrium and controlled by the kinase activity of FYN, which phosphorylates PAG-Tyr317. This phosphorylation allows docking of Csk, which in turn phosphorylates FYN at its C-terminal inhibitory tyrosine, leading to a decrease in FYN activity and thus closing this activation loop [52, 56, 57]. Integrin-mediated hyperphosphorylation of FYN activation and new protein synthesis was observed after stimulation in highly metastatic cells [58]. By activating FYN, HGF/MET promotes the progression of prostate cancer [59, 60]. Both classical Wnt3a and non-classical Wnt5a pathways stimulate Fz2 phosphorylation, FYN activation by Fz2, and FYN-dependent phosphorylation of Stat3 [61]. Hyperphosphorylation of autophosphorylation site tyrosine in FYN was detected in protein tyrosine phosphatase N23 (PTPN23)-deficient breast cancer tumors, confirming that FYN could be a therapeutic target for PTPN23 heterozygous or pure deletion breast tumors [62]. Integrins are involved in triggering FAK-Y397 phosphorylation, and a portion of FAK is located in the lipid raft/fossa structural domain where it interacts with FYN leading to elevated levels of FYN phosphorylation and elevated activity [63]. Microarray transcriptomic and bioinformatic analysis of ovarian cancer identified FYN as a key downstream target in the transcriptome of GNAi2/gip2 regulated tumor progression [64].

The downstream substrates regulated by FYN in tumors and its biologic functions

 Substrates regulated by FYN (Fig. 3)

FYN phosphorylates calmodulin h3 and calmodulin h1 at the Tyr261 and Tyr182 [65]. FYN was also found to phosphorylate AMPKa at Y436 and inhibit its enzymatic activity without affecting the assembly of the heterotrimer complex of AMPK [66]. FYN phosphorylates the IP(3) receptor at the Tyr 353 [67]. One study demonstrated that FYN phosphorylates β-adducin at Tyr-489, located in its C-terminal tail structural domain [68]. The phosphorylation of Sam68 by FYN reverses this action and facilitates the selection of the Bcl-x(L) splicing site [69]. Phosphorylation of Nrf at Tyr-568 by FYN results in nuclear export of Nrf2, binding to Nrf2, and degradation of Nrf2 [70, 71]. The selective regulation of Pyk2 phosphorylation by FYN in vivo correlates with FYN’s preferential phosphorylation of Pyk2 in vitro [72]. FYN phosphorylates AMPK to inhibit AMPK activity and AMP-dependent activation of autophagy, and in addition, FYN directly phosphorylates LKB1 at Y261 and 365, and mutations at these sites result in LKB1 export to the cytoplasm and increase AMPK phosphorylation [66, 73]. 32P radiolabeled in vitro kinase assays displayed phosphorylation of COX2 by FYN, and further studies revealed that phosphorylation of residue Y446 in the COX2 enzyme by FYN resulted in increased enzyme activity without altering the protein level of COX2, which is a direct substrate for phosphorylation by FYN. FYN constitutively associates with and phosphorylates Cas, suggesting that tyrosine phosphorylation of Cas may be catalyzed by FYN [74,75,76]. The Tyr-828 and Tyr-852 sites of the stem cell marker CD133 are phosphorylated in the cytoplasm by FYN tyrosine kinase [77]. It has been demonstrated that increased tyrosine phosphorylation of GSK-3beta directly corresponds to the increased association of FYN, suggesting that FYN may phosphorylate GSK-3beta or mediate phosphorylation of GSK-3beta [78]. Activated FYN kinase phosphorylates histone H3 at Ser-10 [79]. FYN phosphorylates IP3R1 in Tyr353[80]. Phosphorylation of IFITM3 by FYN leads to a decrease in IFITM3 ubiquitination [81]. FYN kinase directly phosphorylates LKB1 at Y261 and Y365, and mutations at these sites result in LKB1 export to the cytoplasm and increased AMPK phosphorylation [73, 82, 83]. FYN phosphorylates Nrf2 Y568, leading to nuclear export and degradation of Nrf2 [84, 85]. Y420 is a major site of phosphorylation of RLK by FYN, and phosphorylation of this site activates RLK kinase [86]. In an in vitro kinase assay, Src and FYN were able to phosphorylate RSK2 directly at Tyr-529 [87].The differential potential of FYN to phosphorylate Sam68 can be controlled by the interaction of the kinase SH3 structural domain with the linker and Sam68, possibly based on competitive binding [88]. FYN phosphorylates and activates ZAP-70, two kinases that cooperate in TCR signaling [89]. FYN drives G6PD by phosphorylating STAT3 expression, leading to the promotion of tumor growth and inhibition of cellular senescence [90]. It has been demonstrated that FYN directly phosphorylates CD147 at Y140 and Y183, while CD147-FF (Y140F/Y183F) mutation impairs the interaction between CD147 and FYN, and knockdown of FYN expression significantly attenuates the malignant phenotype of melanoma cells by downregulating CD147 phosphorylation [91, 92]. FYN interacts with ARHGEF16 to regulate the proliferation and migration of colon cancer cells, and knockdown of FYN expression decreases ARHGEF16 protein levels in colon cancer cells[93]. Inhibition of FYN blocks the phosphorylation level of FAK/N-WASP, which in turn prevents hepatic stellate cell (HSC) activation, proliferation, and migration[94]. In breast cancer cells, FYN knockdown led to reduced phosphorylation of zeta/delta (Thr232) and Cdc25A (Ser124) [95]. Upon EGFR activation, 6PGD is phosphorylated by FYN at tyrosine Y481, and this phosphorylation enhances 6PGD activity, which activates NADPH and PPP of ribose 5-phosphate, thereby detoxifying intracellular reactive oxygen species (ROS) and accelerating DNA synthesis [96]. Inhibition of FYN activity in pancreatic cancer is upregulated by P21-activated kinase 1 expression and promotes phosphorylation and nuclear localization of hnRNP E1, leading to the construction of a spliceosome complex that affects variable splicing of integrin β1 [97]. There is negative reciprocal regulation between SMAD4 and FYN in ovarian tumors, and knockdown of SMAD4 results in elevated levels of FYN expression, and FYN activation leads to dissociation of cell-cell junctions and adhesion, resulting in increased tumor metastasis [98]. FYN affects proliferation, apoptosis, migration, and invasion of pancreatic cancer cells through phosphorylation of GluN2b and regulation of the AKT signaling pathway [99]. In angio-immunoblastogenic T-cell lymphoma (AITL) and peripheral T-cell lymphoma not otherwise specified (PTCL, NOS), the FYN-TRAF3IP2 fusion gene induces aberrant NF-κB signaling downstream of T-cell receptor activation, and inhibition of FYN-TRAF3IP2-induced NF-κB signaling in tumors with an IκB kinase inhibitor provides potent anti-lymphoma effect [100].

Biological functions of FYN kinase in cancer

Current evidence indicates that FYN plays a pro-oncogenic role in cancer development. The role of FYN in cell cycle, cell adhesion, proliferation, metastasis, drug resistance, and intrinsic immunity will be discussed in this section(Fig. 4).

Fig. 4
figure 4

Multiple biological functions of FYN in cancer. Mainly includes the role of FYN in cell cycle, cell adhesion, proliferation, metastasis, drug resistance, and intrinsic immunity

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 FYN regulates the tumor cell cycle

FYN functions as a member of the Src family of kinases to prevent cytoplasmic division after mitosis utilizing anti-SH2, and as a result, cell division is inhibited [101, 102]. It has been demonstrated that FYN regulates mitotic spindle formation through its effect on microtubule polymerization and stabilization.FYN promotes mitotic spindle formation through increased microtubule aggregation, leading to cell formation that accelerates M-phase progression [103]. Insufficient FYN activity has been reported to cause cytoplasmic division failure and prevent mitosis from proceeding [104]. During cytoplasmic division, FYN is localized to the cortical membrane-bound domain depending on its N-terminal length [105]. Cortical FYN is thought to be involved in regulating cytoplasmic division [104]. The above findings suggest that FYN inhibits mitotic progression and blocks pericellular progression.

 FYN regulates tumor cell adhesion

Intercellular adhesion was enhanced by inhibiting FYN activity with dasatinib or silencing FYN [106]. The initial adhesion of T cells follows activation, but it does not require the action of FYN kinase. However, in late cell adhesion, non-catalytically functional FYN is required [107]. Phosphorylated FYN (pTyr530) is upregulated in Integrin α6-deficient acute lymphoblastic leukemia (ALL) and mediates the development of chemoresistance through adhesion [108].

 FYN regulates tumor cell proliferation

FYN is a proto-oncogene belonging to the Src family, which has been reported in many studies to promote cancer cell proliferation and inhibit apoptosis. FYN is an important mediator and regulator of mitogenic signaling cell cycle entry, growth, and proliferation [60]. FYN is upregulated in thyroid cancer at both mRNA and protein expression levels, which promotes cell proliferation and inhibits apoptosis in thyroid cancer [109]. FYN is a direct target of microRNA-125a-3p, which directly inhibits the expression and activity of FYN, and induces cell cycle capture and expression of FYN downstream proteins, which in turn inhibits cell proliferation. This suggests that FYN promotes tumor cell proliferation [23]. In chronic granulocytic leukemia, increased FYN expression and activity promote the transition from chronic granulocytic leukemia to the acute phase and accelerate cell proliferation [110]. FYN induces osteoclast proliferation inhibiting osteoclast apoptosis [111]. FYN expression is dysregulated in acute myeloid leukemia (AML) patient samples, and FYN is associated with wild-type FLT3 and oncogenic FLT3-ITD. This correlation depended on the kinase activity of FLT3 and the SH2 structural domain of FYN. Multiple FYN binding sites were present in FLT3, and FYN expression induced slightly enhanced phosphorylation of AKT, ERK1/2, and p38 and effectively enhanced STAT5 phosphorylation and colony formation. Moreover, higher expression of FYN in combination with FLT3-ITD mutation resulted in enrichment of the STAT5 signaling pathway and was associated with poor prognosis in AML. These results demonstrate that FYN promotes AML cell proliferation by selectively activating the STAT5 pathway in cooperation with oncogenic FLT3-ITD in cell transformation [112]. LINC00152 promotes esophageal squamous cell carcinoma (ESCC) proliferation by downregulating miR-153-3p and promoting FYN expression [29]. In glioblastoma, FYN phosphorylates PIKE-A and thus promotes its binding to AMPK, inhibits the tumor suppressive effect of AMPK, and promotes tumor cell proliferation [113]. Inhibition of FYN activity inhibits pancreatic cancer cell proliferation [114]. Skin squamous cell carcinoma (SCC) cells, increased FYN activity decreases Notch1/NICD mRNA and protein expression levels and promotes STAT3 phosphorylation to induce proliferation and tumorigenesis [115]. FYN phosphorylates STAT3 and promotes G6PD expression, promoting malignant glioma growth and inhibiting cellular senescence [90]. FYN interacts with ARHGEF16 to promote colon cancer cell proliferation [93]. The FYN/STAT3 pathway inhibits melanoma cell growth [116]. FYN stimulates pancreatic cancer progression through phosphorylation of GluN2b and the regulated AKT protein kinase signaling pathway [99]. 5 ‘nucleotidase domain containing 2 (NT5DC2) promotes glioblastoma progression by upregulating FYN expression levels [117].

FYN regulates tumor epithelial-mesenchymal transition (EMT) and metastasis

Epithelial-mesenchymal transition (EMT) is the transformation of acute epithelial cells into adjacent mesenchymal cells that occurs during embryonic transdifferentiation and plays an extremely important role in cancer metastasis [118, 119]. FYN upregulates the expression of mesenchymal markers of breast cancer, epithelial-mesenchymal transition (EMT)-related transcription factors, and downregulates the expression of epithelial cells to induce the development of EMT [120]. It has been revealed that epithelial integrin αvβ6 complexes with FYN kinase in oral SCC promote EMT and migration [121]. miR-125a-3p inhibits epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma (PDAC) by directly targeting FYN [26]. FYN has also been demonstrated to promote EMT and tumor metastasis in colon cancer cells [122].It has been demonstrated that FYN promotes cell migration and invasion by regulating the AMPK / mTOR signaling pathway in CCA cell lines, and therefore knocking down FYN expression levels is an effective option for anti-CCA therapy [123]. In thyroid cancer, FYN can also control tumor cell migration and invasion [109]. The expression of FYN by KLF5 can increase tumor invasion and cell migration in bladder cancer[22]. The DEP-1-FYN reciprocal regulatory loop section promotes the migration of microglia in brain tissue [124]. Ras/PI3K/Akt signaling can increase FYN overexpression in cancer, thereby promoting tumor cell migration and invasion [45].FYN forms a molecular complex with Nck and PAK-2 and p-Tyr molecular complexes with Nck and PAK-2 and assembles in a p-Tyr1214-dependent manner. This triggers activation of the SAPK2/p38 MAP kinase module and promotes endothelial cell migration [125]. Chemoattractant receptor binding induces FYN-dependent PI3K activation bound to LFA-1 and suggests that FYN is required to initiate and/or regulate chemoattractant-mediated LFA-1 activation to promote targeted migration [126]. Inhibition of FYN activity inhibits metastasis in pancreatic cancer [114]. FYN and its downstream molecular signaling pathway proteins are upregulated in prostate cancer expression [127]. FYN promotes the maintenance of the neuroendocrine phenotype of tumor cells in progressive prostate cancer as well as Vascular metastasis of cancer [60]. miR-125a-3p overexpression inhibits the activity of FYN, FAK, and paxillin, thus suppressing prostate cancer metastasis [27]. FYN is recruited to the α6β4/ SHP2 complex by interaction with phospho-Y580 at the C-terminus of SHP2 for activation, and this Y580-SHP2 interaction localizes FYN to the receptor binding site, which is required for α6β4-dependent promotion of invasive metastasis [42]. It has been demonstrated that upregulation of FYN expression is associated with metastasis in human pancreatic cancer. Inhibition of FYN activation by kinase-inactivating FYN transfection in BxPC3 pancreatic cancer cells reduced liver metastasis in nude mice [128]. At this stage, we have revealed that FYN in gastric cancer promotes proliferation and metastasis through phosphorylation of TOPK to enhance its oncogenic activity and activation of TOPK downstream proliferation and metastasis-related signaling pathways. FYN and ARHGEF16 interact to promote the migration of colon cancer cells [93]. Ampelopsins A and C induce cell metastasis by downregulating FYN expression in breast cancer cells [129]. IBSP promotes the growth and invasiveness of colorectal cancer (CRC) by a potential mechanism of activating the FYN/β-catenin signaling pathway [130]. FYN expression is elevated in melanoma cells, and knockdown of FYN significantly inhibits the proliferation and migration of melanoma cells by downregulating CD147 phosphorylation [92]. FYN has been demonstrated to promote gastric cancer metastasis by activating STAT3-mediated epithelial-mesenchymal transition [131]. A TCGA cancer database analysis based on genes related to lipid metabolism in colon adenocarcinoma found that FYN gene expression was associated with the activation of the EMT pathway [132]. It has been shown in another study that increased FYN expression may contribute to hepatocellular carcinoma metastasis [133].The Wnt5-Fzd2-FYN-Stat3 axis contributes to the EMT program, cell migration, and multiple tumor metastases, and the FYN inhibitor Dasatinib inhibits this process [122].

The role of FYN in tumor drug resistance

The emergence of drug resistance remains a formidable challenge for the effective treatment of cancer patients, and several studies have found that FYN promotes drug resistance in tumors. Knockdown of FYN protein expression levels rather than inhibition of its activity sensitizes TKI-resistant cells to dasatinib, a dual BCR-ABL1/Src inhibitor [134]. Knockdown of FYN kinase by pharmacological inhibition or siRNA-mediated re-sensitization of chronic granulocytic leukemia (CML) cells to the BCR-ABL inhibitor imatinib-resistant cell line (IM-R cells) to imatinib [135]. Concurrently, FYN overexpression in the tamoxifen-sensitive group reduced sensitivity to tamoxifen treatment. At the same time, knockdown of FYN expression restored sensitivity to tamoxifen, and mechanistic studies suggested that FYN overcomes the antiproliferative effects of tamoxifen by activating important cell cycle-related proteins [95]. miR-381 promotes the chemosensitivity of breast cancer cells to DOX by downregulating FYN to inactivate MAPK signaling[30]. Overactivation of FYN in dasatinib-resistant cell promotes the development of drug resistance [136]. FYN causes tamoxifen resistance in breast cancer (ER+), and knockdown of FYN expression or use of FYN inhibitors significantly inhibits the growth of tamoxifen-resistant cells and the association with poor prognosis in breast cancer [37]. The involvement of FYN in anticancer drug resistance has been demonstrated, where increased FYN expression was associated with resistance to imatinib in the K562 cell [137]. FYN modulates imatinib resistance in prostate cancer patients through interaction with miR-128/193a-5p/494 [138]. Thus, FYN is highly expressed in several cancer-resistant cell and is involved in developing cancer drug resistance.

FYN and intrinsic immune response

The FYN splice variant (FYNT) was first identified in T lymphocytes, and the development and activation of lymphocytes, macrophages, dendritic cells, and natural killer (NK) cells is enhanced by increased expression or activation of Src and its downstream protein PI3K [12, 17, 139, 140]. One study confirmed that antigen-specific T cell activation depends on FYN activity and its knockdown severely impairs T cell responses [140]. Clinical studies in CML patients treated with dasatinib (a Bcr-Abl tyrosine kinase inhibitor that also inhibits SFKs) revealed transient immunosuppression characterized by IgE-dependent activation of hemophilic and T-cell receptor-dependent activation of T lymphocytes [141]. Another study demonstrated SFK inhibitor effects on patients after dasatinib treatment. The loss of FYN binding to intraluminal leaflets accompanied by lipid perturbation attenuated NK cell activation [142]. FasL overexpression enhances NK and T cell-mediated killing by recruiting FYN through proline-rich domains [143]. FYN in High expression of FYN in glioma cells reduces immune activation against glioma, and inhibition of FYN improves the efficacy of anti-glioma immunotherapy [144]. The FYN-ADAP pathway preferentially regulates cytokine production in NK and T cells [145]. FYN directly binds and phosphorylates ADAP, SKAP55, and SHP-2, while SHP-2 interacts with PD-1 to induce PD-1 + CTLA-4 + CD8 + TIL in tumors [146].

The value of targeted FYN inhibition in cancer therapy

Several compounds have been shown to inhibit the kinase activity of FYN in cancer and have also shown to be of great value in cancer therapy. Most of these compounds are SRC family kinase inhibitors, and some of them also target other kinases, however, there is sufficient evidence to confirm that they may be valuable targets in clinical therapy (Table 1).

Table 1 Clinical trials in the context of SFKs. Data collected from clinicaltrials.gov on 10th Jan 2023
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SFKs inhibitors in clinical studies

Several highly specific FYN inhibitors have been developed and shown to be effective in clinical trials. These inhibitors include mainly Dasatinib, Saracatinib, etc. In the following section, we elaborate on the role that these inhibitors play in cancer treatment.

Saracatinib is a highly specific small molecule inhibitor of SRC family kinases with an IC50 value of 10 nm against FYN. In a phase II clinical trial, Saracatinib was confirmed to act as a metastasis suppressor for prostate cancer in the initial stages [147].The anticancer drug saracatinib inhibits phosphorylation of invasion-associated substrates by inhibiting the SRC kinase, which results in a reduced invasive capacity for head and neck squamous cell carcinomas (HNSCC) [154]. Combined with 5-FU, saracatinib has also been shown to have enhanced antitumor effects in gastric cancer [155].It has shown a strong antitumor effect in preclinical models of Biliary tract carcinoma (BTC) [156]. Additionally, saracatinib can be used by itself or in combination with radiotherapy to treat malignant tumors, such as glioblastoma (GBM) [157].

Dasatinib is a novel and effective multitargeted inhibitor of kinases of the SRC family, as well as several other kinases. In a phase II clinical trial in melanoma, dasatinib was not significantly effective due to poor patient tolerance and dosage reductions in the study [148]. An immunotherapy-plus-dasatinib treatment of mice with liver metastases from colorectal cancer significantly increased immune cell infiltration into the tumor, therefore enhancing anti-tumor immunity [158]. Chemotherapy combined with dasatinib is also significantly more effective in treating tumors than chemotherapy alone [159,160,161]. As a result of its inhibition of multiple targets, dasatinib produces anti-growth, anti-angiogenic, and pro-apoptotic effects in oral cancer [162]. Dasatinib has also been shown to be effective in breast cancer [163, 164]. According to another clinical trial, Dasatinib inhibits T-cell receptor signaling and is therapeutic for Angioimmunoblastic T-cell Lymphoma [165]. An exploratory study in melanoma cell lines found that Dasatinib is anti-proliferative and anti-metastatic, and its combination with chemotherapy may improve responses [166].

Ponatinib is a multitarget inhibitor that targets primarily on Abl, PDGFRα, VEGFR2, FGFR1 and SRC, with an IC50 of 5.4 nM for SRC. It was found that chemotherapy and ponatinib together achieved early and sustained remissions for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia and improved the prognosis for patients [167].Another study of Philadelphia chromosome-positive leukemias also demonstrated significant anti-leukemic activity of ponatinib in terms of disease stage and mutation status [168]. Additionally to its therapeutic effects in CML and Ph + ALL, ponatinib has shown significant antitumor effects in some solid tumors [169, 170].

Bosutinib is a novel dual SRC/Abl inhibitor with an IC50 of 1.2 nM against SRC. A phase 4 clinical trial found that Bosutinib was more effective than TKIs for patients with Ph + CP CML [171, 172]. Bosutinib combined with Pemetrexed would be significantly more effective than either agent alone in metastatic solid tumors [173]. According to another clinical study, bosutinib in combination with chemotherapy significantly enhances antitumor activity in locally advanced or metastatic breast cancer [174]. Bosutinib inhibits the activation of EGFR, therefore reducing the progression of head and neck cancer [175]. In HeLa Cells,Bosutinib produces tumor suppressive effects by inhibiting Src/NF-κB/Survivin expression [176]. Bosutinib also inhibited the proliferation and migration of non-small cell lung cancer (NSCLC) in another study [177].

Repotrectinib is an ALK/ROS1/TRK inhibitor [153] and also a potent SRC inhibitor with an IC50 of 5.3 nM. A significant antitumor effect is observed in non-small cell lung cancer patients treated with repotrectinib [178]. Repotrectinib showed significant antitumor effects in neuroblastoma models and was more effective when combined with chemotherapy [179, 180].

Conclusions and future perspectives

In tumors, FYN is expressed at elevated levels and is involved in many signaling pathways. It phosphorylates downstream signaling proteins, which promotes tumor growth. FYN has been studied in prostate cancer, pancreatic cancer, leukemia, breast cancer, thyroid cancer, bile duct cancer, and other tumors. FYN expression levels of both mRNA and protein were significantly higher in prostate cancer cells than in normal cells. Clinical samples from prostate cancer patients demonstrated that FYN, FAK and PXN expression levels were both increased with significant correlations, hence, FYN might be a prostate cancer molecular target [127]. FYN is downstream of the HGF/MET signaling loop, and HGF can effectively regulate FYN activity, which promotes prostate cancer biology by promoting cell growth and regulating targeted chemotaxis-translocation components in prostate cancer biology [59]. However, it has been demonstrated that the FYN tyrosine kinase gene at chromosome 6q21 is a novel candidate tumor suppressor in prostate cancer and that FYN is downregulated by chromosomal deletion and promoter hypermethylation and expression in prostate cancer [181]. FYN increases prostate cancer cell COX2 activity regardless of changes in COX2 or COX1 protein expression levels. The results of this study depict that FYN phosphorylates human COX2 on Tyr 446 and that the corresponding phosphorylated COX2 activating mutation promotes COX2 activity, and the phosphorylation inactivating mutation prevents the FYN-mediated increase in COX2 activity, which is known to be overexpressed in prostate cancer [182]. Computational analysis of FYN expression in the prostate cancer cell line database demonstrated a correlation between neuroendocrine (NE) markers such as CHGA, CD44, CD56, and SYP expression. FYN contributes to vascular metastasis in progressive prostate cancer [60]. Studies of FYN in prostate cancer have not been entirely consistent, with some studies suggesting that FYN is proliferative and metastatic in prostate cancer, while others suggest that FYN expression is downregulated in prostate cancer and is a tumor suppressor in prostate cancer. However, current studies mainly favor FYN as a proto-oncogene in prostate cancer with oncogenic activity. Second, in breast cancer, detection of FYN levels in clinical samples using immunohistochemical techniques (IHC) revealed that FYN expression levels are significantly higher in breast cancer than in adjacent normal tissues and are an important factor in the poor prognosis of breast cancer [183]. Overexpression of FYN in breast cancer has been reported in the literature, and FYN overexpression promotes cell proliferation, migration, and invasion. In addition, FYN upregulates the expression of mesenchymal markers and epithelial-mesenchymal transition (EMT)-related markers. It downregulates the expression of epithelial markers, and the results suggest that FYN mediates FGF2-induced EMT through FOXO1 transcriptional regulation and via PI3K/AKT and ERK/MAPK pathways [120]. Protein tyrosine phosphatase N23 (PTPN23) is a key player in breast epithelial cells and an inhibitor of cell motility and invasion in breast cancer cells. Knockdown of PTPN23 expression detects tyrosine hyperphosphorylation at the autophosphorylation site in FYN. The overexpression of FYN in breast cancer has been documented, and thus the proliferative phenotype of breast cancer disappears upon inhibition of FYN expression, suggesting that FYN is a downstream molecule of PTPN23 mediating breast carcinogenesis [62]. FYN is required to maintain the basal breast cancer subtype, which is the most aggressive and has mesenchymal features with high metastatic capacity. It has been demonstrated that FYN enhances NOTCH2 activation in basal breast cancer cells through STAT5-mediated upregulation of Jagged-1 and DLL4 NOTCH ligands, thereby contributing to the mesenchymal phenotype. FYN and STAT5 are present at high levels in the positive feedback loop between basal breast cancer cells. FYN directly interacts with STAT5 and increases p-STAT5, which further acts as a transcription factor for FYN [20]. In addition, FYN is associated with tamoxifen resistance in breast cancer, and the above studies establish the role of FYN in promoting tumorigenesis and invasive metastasis in breast cancer. In pancreatic cancer, FYN is associated with tamoxifen resistance. In pancreatic cancer, FYN coordinates with HnRNPA2B1 and Sam68 to regulate apoptosis and promote proliferation and metastasis of pancreatic cancer [184]. Upregulation of FYN expression in pancreatic cancer is associated with pancreatic cancer metastasis, and in pancreatic cancer cells, reduced or absent FYN activity significantly inhibited liver metastasis in nude mice. Active FYN promotes pancreatic cell metastasis by regulating proliferation and apoptosis[128]. It has been demonstrated that Inhibition of FYN activity and/or hnRNP E1 overexpression decreased metastasis in pancreatic cancer cells, and FYN / hnRNP E1 signaling regulated pancreatic cancer metastasis by affecting variable splicing of integrin β1 [97]. Inhibition of FYN expression in pancreatic cancer significantly inhibited proliferation, migration, and invasion of pancreatic cancer cells [29]. In prostate cancer, FYN overexpression, in turn, promotes thyroid cancer cells in colon cancer, and FYN induces early adhesion in colon cancer cells [63]. The next study confirmed that FYN promotes metastatic invasion in colon cancer [122]. In acute lymphoma, FYN interacts with FLT3-ITD to selectively activate STAT5 and induce the transformation of lymphoma cells, and inhibition of FYN may assist in treating patients with acute lymphoma [112]. In addition, FYN expression is associated with acute and chronic leukemia. FYN knockdown or downregulation inhibits the migration and invasion of cholangiocarcinoma cells [123]. However, the relationship between FYN and apoptosis is controversial, and some studies have demonstrated that FYN promotes apoptosis in tumor cells [185]. In advanced neuroblastoma, FYN levels are downregulated and positively correlate with survival in patients with advanced neuroblastoma [186].

However, the current research on the biological role of FYN in tumor inhibition is mainly pro-cancer, but we do not know whether FYN also plays a anti-cancer role in other unstudied tumors. Considering that different tumors have different specificities, studying the role of FYN in other tumors is of great importance. Currently, multiple clinical trials are underway to evaluate inhibitors of FYN/SRC, which not only improve chemotherapy efficacy, [159,160,161, 174], but also significantly enhance the therapeutic response to immunotherapy and radiotherapy[157, 158]. A variety of preclinical studies have also demonstrated that FYN/SRC inhibitors inhibit multiple tumor progressions[155, 156, 162, 166, 175]. Hence, in order to better understand the activation and inactivation of FYN, as well as the regulation of FYN expression in additional molecules, future studies are needed. The use of FYN inhibitors in patients with high expression or elevated FYN activity will help improve survival rates in cancer patients.