Understanding the Molecular Mechanism of miR-877-3p Could Provide Potential Biomarkers and Therapeutic Targets in Squamous Cell Carcinoma of the Cervix

Abstract

No therapeutic targets and molecular biomarkers are available in cervical cancer (CC) management. In other cancer types, micro-RNA-877-3p (miR-877-3p) has been associated with events relevant for CC development. Thus, we aimed to determine miR-877-3p role in CC. miR-877-3p levels were examined by quantitative-PCR in 117 cervical lesions and tumors. Effects on CC cell proliferation, migration, and invasion were evaluated upon anti-miR-877-3p transfection. miR-877-3p dependent molecular mechanism was comprehensively explored by proteomics, dual-luciferase reporter assay, western blot, and immunohistochemistry. Cervical tumors expressed higher miR-877-3p levels than benign lesions. miR-877-3p promoted CC cell migration and invasion, at least partly by modulating cytoskeletal protein folding through the chaperonin-containing T-complex protein 1 complex. Notably, miR-877-3p silencing synergized with paclitaxel. Interestingly, miR-877-3p downregulated the levels of an in silico-predicted target, ZNF177, whose expression and subcellular location significantly distinguished high-grade squamous intraepithelial lesions (HSILs) and squamous cell carcinomas of the cervix (SCCCs). Cytoplasmic ZNF177 was significantly associated with worse progression-free survival in SCCC. Our results suggest that: (i) miR-877-3p is a potential therapeutic target whose inhibition improves paclitaxel effects; (ii) the expression and location of its target ZNF177 could be diagnostic biomarkers between HSIL and SCCC; and (iii) cytoplasmic ZNF177 is a poor-prognosis biomarker in SCCC.

Current understanding on the role of CCT3 in cancer research

“…Saioa Mendaza et al experimentally found that mir-877-3p promotes Squamous Cell Carcinoma of the Cervix (SCCC) cell migration and invasion by regulating cytoskeletal protein folding, mainly through the CCT complex, and that antimir-877-3p increased the expression of CCT3 in SCCC, leading to abnormal folding of actin and microtubulin, thereby impairing cell migration and invasion ability. Overall, CCT3 may be considered a new and promising biomarker that is closely related to the progression, prognosis, and survival of CESC and may become a therapeutic target for CESC (26).…”

Uterine miR-877-3p and let-7a-5p are increased during simulated menstruation in a mouse model

“…The role of let-7a-5p and miR-877-3p in the endometrium is undefined. In cancer, let-7a-5p has been shown to inhibit migration, invasion and epithelial–mesenchymal transition, and miR-877-3p promoted cell proliferation and differentiation ( Duan et al 2019 , Mendaza et al 2021 ). We postulate that these miRNAs fine-tune the endometrial transcriptional response to menstrual hypoxia to ensure timely repair of the denuded endometrial surface and limit menstrual blood loss.…”