Proliferation
Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1/IMP1), a member of the IMP family, binds to the 5’ UTR of IGF2 mRNA [
51]. IGF2BP1 has the most conserved “oncogenic” role in the IGF2BP family and is associated with poor prognosis [
52]. Serum response factor (SRF)-encoding mRNA acts as a downstream target of IGF2BP1, which destabilizes cell identity [
53]. IMP1 is overexpressed in high serous ovarian carcinoma (HGSOC), acts as a novel m6A reader by stabilizing c-MYC mRNA, and then promotes HGSOC progression [
54].
YT521-B homology (YTH) domain-containing proteins, including YTHDF1-3, YTHDF1 and YTHDF2, have been recognized as “readers” that identify m6A modifications [
55]. YTHDF1 is highly expressed in HGSOC and is related to an adverse prognosis in patients. It can act as a m6A reader by specifically binding to the m6A modification of the translation initiation factor EIF3C, augmenting EIF3C translation, and promoting OC progression [
56]. Tripartite motif protein 29 (TRIM29) is aberrantly expressed in some cancers and can act as an oncogene or tumour suppressor [
57]. Our research group also revealed that F-box and WD repeat domain-containing 7 (FBW7) expression is regulated in HGSOC, where it interacts and antagonizes YTHDF2 to alter the expression levels of m6A-modified Bcl-2-modifying factor (BMF) mRNA, thereby affecting cell proliferation [
58].
ELAV-like protein 1 (HuR) is a member of the embryonic lethal abnormal visual system (ELAV) family. The transcriptional repressor ZEB2 not only activates EMT but also promotes the initiation and progression of cancers [
59]. HuR regulates the stability and translation of ZEB2 to affect proliferation [
60]. Translocase of inner mitochondrial membrane 44 (TIMM44), a peripheral membrane protein, is associated with the transport of proteins from the mitochondrial inner membrane to the mitochondrial matrix [
61]. HuR modulates the expression of TIMM44 by stabilizing its mRNA levels, and its expression is correlated with OC cell progression [
62]. E2F2 is a transcription activator that plays an important role in cancer progression [
63]. CircE2F2 can bind to HuR to stabilize E2F2 mRNA and consequently promote OC cell proliferation, glucose metabolism and metastasis [
64].
La-related protein 1 (LARP1) is a highly evolutionarily conserved RBP of the LARP family. It can regulate the stability and translation of mRNAs associated with ribosome biogenesis and cell proliferation [
65]. LARP1 interacts with the 3’ UTRs of BIK (encodes a pro-apoptotic protein) and BCL2 (B-cell lymphoma 2, encodes an anti-apoptotic protein), stabilizes BCL2, and destabilizes BIK with a net effect of promoting OC proliferation [
66,
67].
Heterogeneous nuclear ribonucleoproteins (hnRNPs) have been considered crucial tumour oncogenes related to proliferation and apoptosis. hnRNPA2B1 has two isoforms, hnRNPA2 and hnRNPB1, that regulate different gene expression patterns and phenotypes in various cancers [
68]. HnRNPA2B1 binds to and stabilizes the transcript level of Lin28B, thereby promoting serous ovarian cancer (SOC) cells progression [
69]. In addition, IGF2BP3 targets downstream human copper transporter 1 (hCTR1), induces chemoresistance and is correlated with a poor prognosis in SOC patients [
70].
ESRP1, an epithelial cell RBP, participates in the EMT process by regulating alternative splicing and is associated with a poor prognosis [
71]. Circ-NOLC1 promotes EOC progression by binding to ESRP1 and modulates cell-dependent kinase 1 (CDK1) and Ras homologous family member A (RhoA) expression [
72].
MicroRNAs are small endogenous noncoding RNAs that regulate gene expression by promoting the degradation and/or repressing the translation of their target mRNAs. The first step in miRNA maturation is executed by the Drosha microprocessor, in which the RNase III enzyme Drosha (Drosha) and DiGeorge syndrome critical region gene 8 (DGCR8) are the core components [
73,
74]. DGCR8 can recognize primary miRNAs and promote their methylation with the help of the methylase METTL3 [
75]. Dorsha can also be recruited to double-stranded RNA and thereby produce precursor miRNAs [
76]. The RBP DDX1 belongs to the DEAD-box helicase family, which can promote pri-miRNA maturation and repress OC progression [
75].
Expression of RNA-binding motif protein 3 (RBM3), a member of the glycine-rich RNA binding protein (GRP) family, was highly upregulated in OC tissues and A2780 OC cell lines. RBM3 positively regulates the DNA damage response in OC cells and can act as a novel oncogenic prognostic biomarker for OC patients [
77].
Poly C-binding protein 1 (PCBP1) can bind to the 3’ UTR of the cell cycle inhibitor p27 via its KH1 domain, thereby stabilizing p27 and inhibiting OC progression [
78].
Coiled-Coil Domain Containing protein-124 (Ccdc124) is an mRNA-binding factor related to cell division and ribosome biology. Upregulated Ccdc124 expression was associated with a prolonged prognosis in OC patients [
79].
The RBP of DEAD-Box Helicase 3X-Linked (DDX3X) can be stabilized by RNA Component of Mitochondrial RNA Processing Endoribonuclease (lncRNA RMRP) and promotes Phosphoglycerate dehydrogenase (PHGDH) mRNA translation, thus conferring resistance of OC cells and inhibiting OC progression [
80]. Overexpression of DDX3X can reverse miR-196a-mediated OC progression by activating PTEN expression and suppressing AKT activity [
81].
The plasminogen activator (PA) system plays an important role in the invasion and metastasis of OC, and PA inhibitor type 1 (PAI-1) is the main subtype [
82]. PAI-RBP1 (PAI-1 mRNA-Binding Protein 1) contributes to OC progression by binding and stabilizing PAI-1 mRNA [
83].
Apoptosis
Lin28 has two paralogues, Lin28A and Lin28B. Lin28A positively binds to and upregulates the mRNA encoding Rho-associated coiled-coil containing protein kinase family 2 (ROCK2) and therefore promotes cell proliferation, invasion, and metastasis and inhibits apoptosis in OC cells [
84]. LIN28B is highly expressed in HGSOC and can inhibit OC cell apoptosis by binding to AKT2 mRNA, which is associated with the DNA damage pathway, and promote its expression, regulate FOXO3A protein phosphorylation and decrease the antiapoptotic activity of BIM [
85]. NEAT1 is an abundant lncRNA that has been demonstrated to be an oncogene in multiple cancers. Lin28B enhances the stability of NEAT1, whose expression is upregulated in OC cells and correlated with poor prognosis [
86].
PTB, a member of the heterogeneous nuclear family (hnRNPI), regulates RNA processing and internal ribosome entry (IRES)-mediated translation [
87]. PTB knockdown in OC cells inhibits cell apoptosis by alternative splicing [
88].
Invasion and epithelial-mesenchymal transcription (EMT)
Studies have revealed that IGF2BP1 can promote SRF expression in an M6A-dependent manner by impairing miRNA-directed decay [
89]. These phenomena promote tumour cell growth and invasion in an SRF-dependent manner. Decreased IGF2BP2 levels significantly inhibit the proliferation of OC cells [
90].
LncRNA HOX Transcript Antisense RNA (HOTAIR) is overexpressed in OC, leading to disease progression. HuR binds to the lncRNA HOTAIR, which positively regulates microRNA-373 expression and derepresses the expression of the Ras oncogene family member Rab22a, leading to the promotion of proliferation, migration and invasion [
91]. It can induce paclitaxel resistance by binding to and stabilizing the mRNA encoding TUBB3 (class III b β-tubulin) in competition with miR-200c [
92]. In OVCAR3 OC cells, HuR is highly overexpressed, and it binds to and stabilizes lncRNA nuclear enriched abundant transcript 1 (NEAT1), thereby positively promoting proliferation and invasion [
46]. In addition, HuR contributes to tumour proliferation, migration and tumorigenicity by binding to the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), which acts as a sponge for miR-506 and depresses the apoptosis inhibitor iASPP [
93].
Gastric cancer-associated lncRNA1 (GClnc1) is a long noncoding RNA that plays an indispensable role in metastasis [
94]. Forkhead box protein C2 (FOXC2) activates transcription of NOTCH1 by binding to GClnc1, thereby enhancing proliferation and EMT in OC cells [
95].
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a lncRNA whose expression is upregulated in OC and correlated with metastasis. Knockdown of MALAT1 expression can downregulate the splicing factor RBP Fox-1 Homologue 2 (RBFOX2) and subsequently regulate the transcription of tumour suppressor Kinesin family member 1B (KIF1B) [
96].
Sorbin and SH3 domain-containing 2 (SORBS2), which is localized to the 4q35 region of the human genome, participates in signal transduction and cytoskeleton establishment [
97]. Suppression of SORBS2 promotes cell migration by contributing to pseudopodia elongation and detachment of actin from focal adhesion areas [
98]. SORBS2 can stabilize the tumour-suppressive immunomodulatory transcripts WAP four-disulfide core domain 1 (WFDC1) and interleukin-17D (IL-17D), thereby suppressing metastatic colonization of OC cells [
99].
Our recent study indicates that CELF2 expression is positively correlated with the OS and PFS of OC patients. CELF2 increases the stability of its downstream target FAM198B by binding to AU/U-rich elements (AREs) in the 3’ UTR, modulating the proliferation, migration and invasion of OC cells in vivo and in vitro. In addition, we also demonstrate that CELF2/FAM198B can repress the progression of OC via its effects on mitogen-activated protein kinase/extracellular-regulated protein kinase (MAPK/ERK) signalling [
10].
Quaking isoforms 5 (QKI5) had been implicated in the processing of microRNA (miRNA) and pre-mRNA and was downregulated in several cancers, including SOC. Studies have also demonstrated that QKI5 could inhibit metastasis by targeting transcriptional coactivator PDZ (TAZ). Mechanistically, QKI5 bound to TAZ mRNA and recruited EDC4, thus decreasing the stability of TAZ mRNA [
100].
Chemotherapy resistance
IGF2BP1 regulates chemoresistance in OC by stabilizing c-MYC and adenosine triphosphate (ATP)-dependent efflux pump MDR1 (multi-drug-resistance factor 1) [
101].
Lin28B induces chemoresistance, and is correlated with a poor prognosis in HGSOC patients, by targeting downstream human copper transporter 1 (hCTR1) [
70].
SFPQ (PSF, polypyrimidine tract binding protein-associated splicing factor) is a splicing factor that participates in the processes of RNA transport and apoptosis [
102]. SFPQ knockdown increases platinum plus taxane-based chemotherapy (PT)-induced apoptosis by regulating alterative splicing of caspase-9 mRNA in EOC cells [
103].
Cytoplasmic polyadenylation element binding protein 4 (CPEB4) has already been proven to be an RBP that contributes to transcript-level polyadenylation and translation. It binds to Taxol (paclitaxel)-resistance-associated gene-3 (TRAG-3/CSAG2), contributes to its translation, and promotes paclitaxel resistance in OC patients [
104]. CSAG2 was demonstrated necessary for proliferation and tumorigenesis in vivo and CSAG2-stimulated SIRT1 activity to enhance p53 deacetylation was shown to inhibit p53 transcriptional activity, leading to improved cell survival under genotoxic stress [
105]. Thus, interfering CPEB4/CSAG2 axis might be of benefit to overcome paclitaxel-resistant OC.
Y-box binding protein 1 (YBX1/YB1), a member of the cold-shock domain-containing protein family, positively regulates resistance to cisplatin and correlates with the prognosis of EOC patients [
106].
RNA-binding motif protein 3 (RBM3) is associated with a favourable prognosis of OC patients and has been verified to be a positive predictor of overall survival (OS) and relapse-free survival (RFS) [
107]. In addition, increased RBM3 expression promotes platinum sensitivity by regulating the apoptosis-related mediators BCL-2, BAX and DNA integrity, which are involved in DNA damage, and repairs adverse cytotoxic effects after chemotherapy [
3].