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Paradoxical effects of cellular senescence-inhibited gene involved in hepatocellular carcinoma migration and proliferation by ERK pathway and mesenchymal-like markers

Authors Cheng Q, Tong TJ, Li Z, Hu S, Chen D, Wang SQ, Zhu JY

Received 23 September 2018

Accepted for publication 3 January 2019

Published 15 March 2019 Volume 2019:12 Pages 2035—2046


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 2

Editor who approved publication: Dr Sanjeev Srivastava

Qian Cheng,1 Tan-jun Tong,2 Zhao Li,1 Shi-hua Hu,1 Ding-bao Chen,1 Si-qi Wang,1 Ji-ye Zhu1

1Peking University Institute of Organ Transplantation, Peking University Center of Liver Cancer Diagnosis and Treatment, Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Department of Hepatobiliary Surgery, Peking University People’s Hospital, Beijing, 100044, China; 2Peking University Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, 100191, China

Background: Cellular senescence-inhibited gene (CSIG) strongly prolongs the progression of replicative senescence. However, roles and mechanisms of CSIG in tumor progression have not been studied widely.
Methods: Roles of CSIG in migration and proliferation of SMMC7721 and Huh7 cells were analyzed by transwell or cell viability assays, respectively. Tumorigenicity assays were used to study whether CSIG knockdown could affect SMMC7721 proliferation in vivo. Next, Western blotting and RT-PCR were preformed to evaluate the effects of CSIG on P-ERK cascade and epithelial mesenchymal transformation markers. Then, the location and expression of CSIG protein was detected by immunofluorescence and Western blotting, respectively. Finally, the Cancer Genome Atlas dataset was used to analyze CSIG mRNA levels in hepatocellular carcinoma (HCC) and adjacent non-tumor tissues.
Results: In this study, we found that CSIG overexpression promoted SMMC7721 cell migration, and CSIG knockdown suppressed tumorigenicity of SMMC7721 cells. In contrast to expectation, CSIG up-regulation could significantly inhibit Huh7 cell growth and migration. CSIG could promote P-ERK activation and levels of mesenchymal-like markers in SMMC7721 cells, whereas CSIG suppressed P-ERK activation and levels of mesenchymal-like markers in Huh7 cells. CSIG protein was located in nucleoli as well as nucleoplasm of SMMC7721 cells, whereas CSIG protein was mainly expressed in the nucleoli rather than nucleoplasm of Huh7 cells. Finally, due to individual differences, raised or down-regulated trends of CSIG in HCC as compared with adjacent non-tumor tissues are different among various patient populations.
Conclusion: In summary, these results indicate that CSIG might play different roles in SMMC7721 and Huh7 cells through regulating P-ERK pathway and mesenchymal-like markers. The differential distribution of CSIG might be an important factor that causes its different functions in SMMC7721 and Huh7 cells. CSIG might play different roles in various patient populations.

Keywords: cellular senescence-inhibited gene, hepatocellular carcinoma, migration, proliferation, P-extracellular regulated protein kinases, mesenchymal-like markers

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