MiR-223-5p works as an oncomiR in vulvar carcinoma by TP63 suppression
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Beatriz de Melo Maia1,2, Iara Santana Rodrigues1, Erica Mie Akagi1, Nayra Soares do Amaral1, Hui Ling2, Paloma Monroig2, Fernando Augusto Soares1, George Adrian Calin2,3, Rafael Malagoli Rocha4
1Molecular Morphology Laboratory, Anatomic Pathology Department, AC Camargo Cancer Center, São Paulo, Brazil
2Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
3The Center for RNA Interference and Non-Coding RNAs, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
4Gynecology Laboratory, Gynecologic Department Federal University of São Paulo, São Paulo, Brazil
Rafael Malagoli Rocha, email: [email protected]
Keywords: vulvar cancer, microRNAs, cellular assays, hsa-miR-223-5p, TP63
Received: January 11, 2016 Accepted: May 08, 2016 Published: June 23, 2016
MiR-223-5p has been previously mentioned to be associated with tumor metastasis in HPV negative vulvar carcinomas, such as in several other tumor types. In the present study, we hypothesized that this microRNA would be important in vulvar cancer carcinogenesis and progression. To investigate this, we artificially mimicked miR-223-5p expression in a cell line derived from lymph node metastasis of vulvar carcinoma (SW962) and performed in vitro assays. As results, lower cell proliferation (p < 0.01) and migration (p < 0.001) were observed when miR-223-5p was overexpressed. In contrast, increased invasive potential of these cells was verified (p < 0.004). In silico search indicated that miR-223-5p targets TP63, member of the TP53 family of proteins, largely described with importance in vulvar cancer. We experimentally demonstrated that this microRNA is capable to decrease levels of p63 at both mRNA and protein levels (p < 0.001, and p < 0.0001; respectively). Also, a significant inverse correlation was observed between miR-223-5p and p63 expressions in tumors from patients (p = 0.0365). Furthermore, low p63 protein expression was correlated with deeper tumor invasion (p = 0.0491) and lower patient overall survival (p = 0.0494). Our study points out miR-223-5p overexpression as a putative pathological mechanism of tumor invasion and a promising therapeutic target and highlights the importance of both miR-223-5p and p63 as prognostic factors in vulvar cancer. Also, it is plausible that the evaluation of p63 expression in vulvar cancer at the biopsy level may bring important contribution on prognostic establishment and in elaborating better surgical approaches for vulvar cancer patients.
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