Tandrima Mitra

Identification and validation of miR-21 key genes in cervical cancer through an integrated bioinformatics approach

Cervical cancer is one of the most prevalent female reproductive cancers. miR-21 is a multi-target oncomiR that has shown its potential in regulating several cancers including colon, pancreatic, breast, prostate, ovarian, and cervical cancer. However, the signaling network of miR-21 remains underexplored, and only a limited number of miR-21 gene targets in cervical cancer have been reported. In this context, the present study was undertaken to evaluate the role of miR-21 in cervical cancer by combining in silico analysis with in vitro validation in cervical cancer cells. The miR-21 target genes were predicted using four different prediction tools: miRWalk, DIANA, miRDB, and TargetScan. A total of 113 overlapping target genes, common in at least three of the prediction tools, were shortlisted and subjected to functional enrichment analysis. The analysis predicted that JAK-STAT, MAPK, neurotrophin, and Ras signaling pathways are significantly (p≤0.05) targeted by miR-21. The MCODE plugin identified the potential cluster in the protein-protein interaction network based on the highest degree of connectivity. After GEPIA2 validation of all 20 hub genes, NTF3, LIFR, and IL-6R were shortlisted for validation in cervical cancer cell lines. The results showed that NTF3, LIFR, and IL-6R were significantly upregulated in the miR-21 knockdown CaSki cell lines in 6.27, 1.92 and 1.71 folds (p≤0.01), respectively. Similarly, in HeLa cell lines expression of NTF3, LIFR, and IL-6R were overexpressed in 4.06, 5.65, 2.42 folds (p≤0.001), respectively. Findings of the study was confirming the role of miR-21 in regulating the expression of these genes. Additionally, the knockdown of miR-21 significantly inhibited the secretion of matrix metalloproteinases by CaSki cells. These results highlight that miR-21 could be a potential therapeutic target for cervical cancer, although further preclinical and clinical studies are required to validate its role and efficacy.

Cervical cancer development, chemoresistance, and therapy: a snapshot of involvement of microRNA

Cervical cancer (CC) is one of the leading causes of death in women due to cancer and a major concern in the developing world. Persistent human papilloma virus (HPV) infection is the major causative agent for CC. Besides HPV infection, genetic and epigenetic factors including microRNA (miRNA) also contribute to the malignant transformation. Earlier studies have revealed that miRNAs participate in cell proliferation, invasion and metastasis, angiogenesis, and chemoresistance processes by binding and inversely regulating the target oncogenes or tumor suppressor genes. Based on functions and mechanistic insights, miRNAs have been identified as cellular modulators that have an enormous role in diagnosis, prognosis, and cancer therapy. Signatures of miRNA could be used as diagnostic markers which are necessary for early diagnosis and management of CC. The therapeutic potential of miRNAs has been shown in CC; however, more comprehensive clinical trials are required for the clinical translation of miRNA-based diagnostics and therapeutics. Understanding the molecular mechanism of miRNAs and their target genes has been useful to develop miRNA-based therapeutic strategies for CC and overcome chemoresistance. In this review, we summarize the role of miRNAs in the development, progression, and metastasis of CC as well as chemoresistance. Further, we discuss the diagnostic and therapeutic potential of miRNAs to overcome chemoresistance and treatment of CC.