Abstract
Simple SummaryCervical cancer (CC) is managed mainly using subjective and conventional methods. Research about the molecular mechanisms of micro-RNA-877-3p (miR-877-3p) in other cancer types revealed that it interacts with events that are important for CC. Our aim was to understand the role of miR-877-3p in CC. We observed that it was overexpressed in cervical tumors compared with benign lesions, and that it promoted CC cell migration and invasion by modulating cytoskeletal protein folding, which potentiated the effects caused by paclitaxel, one of the most common therapeutic drugs used in CC. We demonstrated a functional link between miR-877-3p and one of its predicted targets, ZNF177. The expression and subcellular location of ZNF177 objectively distinguished two CC entities and predicted poor outcome in the most aggressive form. Therefore, the understanding of the molecular mechanisms driven by miR-877-3p provides useful tools for CC clinical management, currently lacking of molecular biomarkers and targeted therapies.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.
Highlights
According to the World Health Organization, cervical cancer (CC) is the fourth most frequent tumor type among women worldwide, and has a five-year survival of 57–67%in Europe [1,2]
After transfection into 293T cells, we found thatexpression the anti-miR-877-3p and that the increase was more pronounced in the wt than in the mut was able to significantly induce luciferase expression compared with the negative control anti-miR (NC), and that3′UTR
While aware of the low number of cases studied, these results indicate that cytoplasmic zinc finger protein 177 (ZNF177) expression and subcellular location could be used to predict diagnosis and prognosis in cervical malignancies
Summary
According to the World Health Organization, cervical cancer (CC) is the fourth most frequent tumor type among women worldwide, and has a five-year survival of 57–67%in Europe [1,2]. Practice Guidelines [2], while surgery is indicated for patients with local/locoregional disease, chemoradiotherapy involving paclitaxel and cisplatin combined with bevacizumab is considered the preferred first-line regimen in metastatic or recurrent CC, with a highest median overall survival of only 16.8 months These drawbacks are serious in the management of two stages of CC development: high-grade squamous intraepithelial lesion (HSIL) and squamous cell carcinoma of the cervix (SCCC). If the infection persists in dividing cells, the lesion can evolve towards an HSIL At this stage, if some molecular alterations arise concomitantly, the tumor may invade the basement membrane of the epithelium and become an SCCC [3,6]. Prognostic, and therapeutic approaches are needed if the current weaknesses of CC clinical management are to be overcome and the life expectancy of these patients improved
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