Abstract
PurposePersistent infection with high-risk human papillomavirus (HR-HPV) is thought to play a prominent role in the initiation and progression of almost all cases of cervical cancer. Previously, we and others found that microRNA 34a (miR-34a) may be regulated by HR-HPV E6 to contribute to the development of cervical cancer. Here, we aimed to identify the oncogenic potential and clinical significance of a known miR-34a target, WNT1, in cervical squamous cell carcinoma (SCC) development and to investigate the associated mechanisms underlying cervical SCC cell proliferation and invasion.MethodsWNT1 and miR-34a expression levels were assessed in primary cervical lesions using immunohistochemistry and qRT-PCR, respectively. The cellular effects and the expression of its associated genes were examined in cervical SCC-derived Siha and Caski cells after siRNA-WNT1 (downregulation) or miR-34a mimic (upregulation) treatment. A cervical SCC xenograft mouse model was used to investigate the in vivo effects of miR-34a overexpression. HPV-16 E6/E7 expression was inhibited by gene promoter siRNA targeting, after which the levels of miR-34a and WNT1 were examined.ResultsWNT1 protein upregulation was found to be associated with a poor prognosis in cervical SCC patients. In vitro assays in Siha and Caski cells revealed that WNT1 downregulation decreased cell proliferation and invasion, inhibited WNT/β-catenin activation and affected the expression of E-cadherin and P-cadherin. MiR-34a upregulation resulted in decreased WNT1 expression. An inverse correlation between miR-34a and WNT1 expression was also observed in primary cervical SCC tissues. In addition, we found that MiR-34a could regulate an E-cadherin to P-cadherin switch (E-P cadherin switch) to inhibit cell proliferation and tumorigenesis in vitro and in vivo via inactivation of the WNT1/β-catenin pathway. Finally, we found that decreased HPV-16 E6/E7 expression resulted in miR-34a upregulation and WNT1 downregulation in Siha and Caski cells.ConclusionsFrom our results we conclude that WNT1, as a target of miR-34a, can promote cervical SCC cell proliferation and invasion by induction of an E-P cadherin switch via the WNT1/β-catenin pathway. Our results may provide new options for the treatment of patients with cervical SCC.
Highlights
Cervical cancer is one of the most common malignancies in females with over 527,000 new cases and 265,000 deaths worldwide per year [1, 2]
We examined the expression of WNT family member 1 (WNT1) in normal cervical epithelium and cervical squamous cell carcinoma (SCC) tissues, and explored the effect of decreased WNT1 expression on cervical SCC cell behavior and the expressions of E-cadherin and Pcadherin, as well as the expression of molecules associated with the WNT/β-catenin pathway in HPV-16 positive cervical SCC-derived cell lines
Four-micron-thick sections were obtained from paraffinembedded tissues and, subsequently, incubated with a primary antibody directed against WNT1 for 1 h at room temperature
Summary
Cervical cancer is one of the most common malignancies in females with over 527,000 new cases and 265,000 deaths worldwide per year [1, 2]. HR-HPV E6/E7 can cause the degradation of p53 and retinoblastoma tumor suppressor family members to promote cell proliferation and invasion and to inhibit apoptosis [3] It plays an important role in regulating the expressions of downstream genes, microRNAs (miRNAs) and signaling pathways, the exact mechanisms by which HR-HPV E6/E7 induces cervical cancer initiation and progression are not yet fully elucidated. We found that exogenous expression of HPV-16 E6/E7 in cervical cell lines significantly increased P-cadherin levels and decreased Ecadherin levels, leading to an E-cadherin to Pcadherin switch (E-P cadherin switch) [8] These results indicate that HPV-16 E6/E7 may be involved in cervical cancer initiation and progression by regulating the E-P cadherin switch. The exact role of HPV-16 E6/E7 in the E-P cadherin switch in SCC has so far remained unexplored
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