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Knockdown of RNF6 inhibits gastric cancer cell growth by suppressing STAT3 signaling

Authors Huang Z, Cai Y, Yang C, Chen Z, Sun H, Xu Y, Chen W, Xu D, Tian W, Wang H

Received 21 May 2018

Accepted for publication 20 August 2018

Published 5 October 2018 Volume 2018:11 Pages 6579—6587

DOI https://doi.org/10.2147/OTT.S174846

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 4

Editor who approved publication: Dr Arseniy Yuzhalin


Ziming Huang,1 Yong Cai,1 Chenchen Yang,1 Zhen Chen,1 Hong Sun,1 Yingying Xu,2 Wei Chen,3 Dafu Xu,4 Wenze Tian,4 Haixiao Wang5

1Department of Emergency Surgery, The Affiliated Huaian No 1 People’s Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu, China; 2Department of Radiotherapy, The Affiliated Huaian No 1 People’s Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu, China; 3Department of Respiratory Care, The Affiliated Huaian No 1 People’s Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu, China; 4Department of Cardiothoracic Surgery, The Affiliated Huaian No 1 People’s Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu, China; 5Department of General Surgery, The Affiliated Huaian No 1 People’s Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu, China

Background and objective: RNF6, an E3 ligase, has been reported to play an important role in the tumorigenesis in several tissues, but its role in gastric cancer is still unknown. In this study, we aimed to investigate the biological function and molecular mechanisms of RNF6 in gastric cancer.
Materials and methods: The expression levels of RNF6 were detected by quantitative real-time PCR (qRT-PCR) and immunoblotting in gastric cancer tissues and cell lines. Cell Counting Kit-8 assay was performed to evaluate cell proliferation. Cell apoptosis was analyzed by flow cytometer and immunoblotting. Luciferase assay, immunoblotting and qRT-PCR were performed to explore the activation of STAT3. Immunoprecipitation was performed to evaluate the ubiquitination of SHP-1.
Results: In this study, RNF6 was found to be upregulated in both primary tissues and cell lines of gastric cancer. Knockdown or overexpression of RNF6 inhibited or promoted cell growth of gastric cancer cells. Knockdown of RNF6 also induced the cleavage of PARP and promoted cell apoptosis in gastric cancer cells. In addition, knockdown of RNF6 also increased the cytotoxicity of doxorubicin against gastric cancer. Moreover, knockdown of RNF6 inhibited STAT3-derived luciferase activity and downregulated the phosphorylation of STAT3, but upregulated the protein level of SHP-1. Knockdown of RNF6 downregulated the expression of MCL1 and XIAP, which are target genes of STAT3. Further studies showed that RNF6 regulated the stability of SHP-1 by inducing its polyubiquitination.
Conclusion: These results demonstrated that RNF6 was highly expressed in gastric cancer and regulated the growth of gastric cancer cells by affecting SHP-1/STAT3 signaling, which suggested that RNF6 could be a novel target for gastric cancer therapy.

Keywords: RNF6, cell growth, gastric cancer, STAT3, SHP-1

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