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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2018.00538

SIRT6 is involved in the progression of ovarian carcinomas via β-catenin-mediated epithelial to mesenchymal transition

Jun Sang Bae1, Sang Jae Noh1, Kyoung Min Kim1,  See-Hyoung Park2,  Usama K. Hussein1, 3, Ho Sung Park1*, Byung-Hyun Park1,  Sang Hoon Ha1, Ho Lee1, Myoung Ja Chung1, Woo Sung Moon1, Dong Hyu Cho1, 4 and  Kyu Yun Jang1, 4*
  • 1Department of Pathology, Chonbuk National University, South Korea
  • 2Department of Bio and Chemical Engineering, Hongik University, South Korea
  • 3Faculty of Science, Beni-Suef University, Egypt
  • 4, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Chonbuk National University Hospital, South Korea

SIRT6 is involved in various cellular signaling pathways including those involved in tumorigenesis in association with β-catenin. However, the role of SIRT6 in tumorigenesis has been controversially reported and the studies on the role of SIRT6 in ovarian cancers is limited. In this study, we evaluated the expression and roles of SIRT6 in conjunction with the expression of active β-catenin in 104 human ovarian carcinomas and ovarian cancer cells. In human ovarian carcinomas, the expressions of SIRT6 and active β-catenin were associated with higher tumor stage, higher histologic grade, and platinum-resistance. Moreover, nuclear expression of SIRT6 (104 ovarian carcinomas; P = 0.010, 63 high-grade serous carcinomas; P = 0.040) and activated β-catenin (104 ovarian carcinomas; P = 0.013, 63 high-grade serous carcinomas; P = 0.005) were independent indicators of shorter overall survival of ovarian carcinoma patients in multivariate analysis. In OVCAR3 and OVCAR5 ovarian cancer cells, knock-down of SIRT6 significantly inhibited the migration and invasion of cells, but did not inhibit the proliferation of cells. SIRT6-mediated invasiveness of ovarian cancer cells was associated with the expression of epithelial-to-mesenchymal transition-related signaling molecules such as snail, vimentin, N-cadherin, E-cadherin, and activated β-catenin. Especially, SIRT6-mediated increase of invasiveness and activation of epithelial-to-mesenchymal transition signaling was attenuated by knock-down of β-catenin. In conclusion, this study suggests that SIRT6-β-catenin signaling is involved in the epithelial-to-mesenchymal transition of ovarian cancer cells, and the expression of SIRT6 and active β-catenin might be used as indicators of poor prognosis of ovarian carcinoma patients. In addition, our results suggest that SIRT6-β-catenin signaling might be a new therapeutic target of ovarian carcinomas.

Keywords: Ovary, Carcinoma, SIRT6, b-catenin, prognosis

Received: 04 Aug 2018; Accepted: 01 Nov 2018.

Edited by:

Rebecca Stone, Johns Hopkins Medicine, United States

Reviewed by:

Sophia H. George, University of Miami, United States
Guillermo N. Armaiz Pena, Ponce Research Institute, Ponce Health Sciences University, Puerto Rico  

Copyright: © 2018 Bae, Noh, Kim, Park, Hussein, Park, Park, Ha, Lee, Chung, Moon, Cho and Jang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Ho Sung Park, Chonbuk National University, Department of Pathology, Jeonju, 561-756, North Jeolla, South Korea, hspark@jbnu.ac.kr
Prof. Kyu Yun Jang, Chonbuk National University, Department of Pathology, Jeonju, 561-756, North Jeolla, South Korea, kyjang@chonbuk.ac.kr