A number of studies have revealed that elements of m6A RNA methylation involve complicated mechanisms that participate in the induction and development of multiple cancer types, such as hepatocellular carcinoma, breast and pancreatic cancer, and so on [21, 22]. Therefore, we hypothesized that changes in the abundance of expression of these elements might be potential prognostic biomarkers for CC.
To explore the best candidates among all THE m6A-related players, the 2 CC datasets were surveyed and ZC3H13 and FMR1 were found to be the most commonly altered genes involved in m6A dynamics in CC. Remarkably, CC samples displayed higher ZC3H13 and FMR1 transcript expression levels compared to NCs in both cohorts. The 2 m6A related genes have already been documented, but their roles in tumor inhibition and progression remain unclear. Zhu et al. found that ZC3H13 was associated with cell proliferation and invasion in colorectal cancer [23]. In contrast, the another m6A regulators have not been proven to be associated with cancer (FMR1) according to our extensive PubMed search. However, both were significantly associated with a patient’s prognosis in CC. ZC3H13 (Zinc Finger CCCH-Type Containing 13) is a protein encoding gene and related component of the WMM complex, which is important for m6A methylation of mRNAs and can promote the efficiency of mRNA splicing and RNA processing at 3'-UTR [23]. The expression of ZC3H13 was upregulated in CC samples and was found to be an independent prognostic factor for OS. In contrast, FMR1 was were downregulated in CC samples and upregulated expression of them may be positively associated with OS. Furthermore, multivariable Cox regression analysis verified their prognostic role in CC. FMR1 was shown to regulate alternative splicing that specifically recognizes and binds to m6A-containing RNAs. GO and KEGG analysis showed that the 2 subgroups not only were significantly correlated with clinical pathologicy but also with biological processes and pathways, such as cluster1 which was mostly enriched during endocytosis and mRNA surveillance, while cluster 2 was correlated with many cancer-related pathways, such as PI3K-Akt signaling and microRNAs in cancer pathways. The PI3K-Akt signaling pathway has been reported to be associated with different types of cancer by Deng et al. It is known that activation of the PI3K-Akt signaling pathway causes DNA damage, epithelial-mesenchymal transition and cancer stem cell promotion in ovarian cancer (OV) [25; 26]. In CC, inhibition of the PI3K/AKT signaling pathway can suppress tumor progression [27].
A 2-gene risk prognostic model based on m6A target genes for predicting OS of CC patients was developed. Patients were divided into high-risk and low-risk groups based on the risk score calculated by the 2-m6A related gene risk model. Survival, ROC curves and nomogram analysis indicated that the 2-m6A related gene risk prognostic model had high predictive accuracy. ZC3H13 and FMR1 transcript levels accurately discriminated between NCs and CCs, and may well serve as novel biomarkers for patient management. Multivariable Cox regression analysis proved that the risk score is an independent prognostic marker that predict the clinical pathological features of CC.
To explore the m6A regulatory mechanism in biological procession, we predicted the related microRNAs of the 20 m6A target genes in the Funrich database and constructed a complex miRNA-mRNA regulatory network. We found that these m6A target genes expression levels were directly regulated by many microRNAs, including mir-23a/b, mir-4262 and mir-30c/e. A number of studies have indicated that these microRNAs were significantly interrelated with cervical cancer procession. Several dysregulated microRNAs have been previously reported to exert their functions via miRNA-mRNA regulatory mechanisms, by dysregulation of ZC3H13, FMR1 activity [28]. Here, we built a miRNA-mRNA regulatory network that may be involved in the progression of CC, but further research is required to elucidate the molecular mechanisms involved.
There were a number of limitations to the present study. First, the clinical data of our samples were not complete. Second, the interaction of microRNA and mRNA was predicted by software, and requires further studies. Third, there was a lack of verification of animal experiments, thus further research is needed to support our study conclusions.
In conclusion, our work has proven that m6A RNA modification is significant for tumor initiation and progression of CC and its related genes. In particular, FMR1 and ZC3H13 may be potential prognostic biomarkers and be useful for the development of an effective treatment strategy for CC.