Let-7i-5p, miR-181a-2-3p and EGF/PI3K/SOX2 axis coordinate to maintain cancer stem cell population in cervical cancer

Abstract

The characteristics of cancer stem cells (CSCs) and the genes responsible for their maintenance are highly variable in different cancers. Here, we identify the coordination among miRNAs and EGF pathway genes which is critical for the maintenance of CSCs in cervical cancer. The transcript analysis of CSCs enriched from cervical cancer cell lines (CaSki and HeLa) revealed a significant upregulation of SOX2. Since EGF receptor is frequently over expressed in cervical cancer, we hypothesized that EGF pathway may be responsible for the upregulation of SOX2. Also, the media used for CSC enrichment was supplemented with EGF. The hypothesis was validated as inhibiting the EGF/PI3K pathway suppressed the expression of SOX2 and reduced the CSC population. In addition, miRNA profiling identified miR-181a-2-3p and let-7i-5p as markedly reduced in CSCs. The exogenous expression of either of these miRNAs in CaSki cells inhibited the expression of SOX2 and subsequently reduced CSC population. In conclusion, this study highlights for the first time the contrasting role of let-7i-5p/miR-181a-2-3p and EGF/PI3K/SOX2 axis in maintaining cervical CSCs. While the EGF pathway promotes CSC formation in cervical cancer by inducing SOX2, miR-181a-2-3p/let-7i-5p counteracts the EGF pathway by inhibiting SOX2, thereby reducing the CSC population.