Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 21, 2015; 21(35): 10137-10149
Published online Sep 21, 2015. doi: 10.3748/wjg.v21.i35.10137
IGF-1 promotes the growth and metastasis of hepatocellular carcinoma via the inhibition of proteasome-mediated cathepsin B degradation
Tian Lei, Xie Ling
Tian Lei, Department of Gastroenterology, the First Affiliated Hospital of Liaoning Medical University, Jinzhou 121000, Liaoning Province, China
Xie Ling, Department of Anatomy, Liaoning Medical College, Jinzhou 121000, Liaoning Province, China
Author contributions: Lei T performed the majority of experiments, analyzed the data and wrote the paper; Ling X participated in treatment of animals.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of the First Affiliated Hospital of Liaoning Medical University.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the First Affiliated Hospital of Liaoning Medical University.
Conflict-of-interest statement: All the authors declare that they have no conflicts of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Tian Lei, MD, Department of Gastroenterology, the First Affiliated Hospital of Liaoning Medical University, Renming Road, Jinzhou 121000, Liaoning Province, China. tljinzhou@163.com
Telephone: +86-416-3123564 Fax: +86-416-3123564
Received: March 1, 2015
Peer-review started: March 2, 2015
First decision: April 20, 2015
Revised: May 17, 2015
Accepted: June 15, 2015
Article in press: June 15, 2015
Published online: September 21, 2015
Abstract

AIM: To investigate the molecular mechanisms of the high IGF-1 level linking diabetes and cancers, which is a risk factor.

METHODS: We used cell growth, wound healing and transwell assay to evaluate the proliferation and metastasis ability of the hepatocellular carcinoma (HCC) cells. Western blot and reverse transcription polymerase chain reaction were used to assess a previously identified lysosomal protease, cathepsin B (CTSB) expression in the HCC cell lines. C57 BL/6J and KK-Ay diabetic mice are used to detect the growth and metastasis of HCC cells that were depleted with or without CTSB shRNA in vivo. Statistical significance was determined by Student’s t-test.

RESULTS: IGF-1 promoted the growth and metastasis of the HCC cell lines via its ability to enhance CTSB expression in both a time-dependent and concentration-dependent manner. HCC cells grew much faster in diabetic KK-Ay mice than in C57 BL/6J mice. Additionally, more metastatic nodules were found in the lungs of KK-Ay mice than the lungs of C57 BL/6J mice. CTSB depletion protects against the tumor-promoting actions of IGF-1 in HCC cells, as well tumor growth and metastasis both in vitro and in vivo. IGF-1 did not change the mRNA levels of CTSB but prolonged the half-life of cathepsin B in Hepa 1-6 and H22 cells. Our results showed that IGF-1 promotes the growth and metastasis of the HCC cells most likely by hindering CTSB degradation mediated by the ubiquitin-proteasome system (UPS), but not autophagy. Overexpression of proteasome activator 28, a family of activators of the 20S proteasome, could not only restore IGF-1-inhibited UPS activity but also decrease IGF-1-induced CTSB accumulation.

CONCLUSION: Our study demonstrates that IGF-1 promotes the growth and metastasis of hepatocellular carcinoma by inhibition of proteasome-mediated CTSB degradation.

Keywords: IGF-1, Cathepsin B, Ubiquitin-proteasome system, Hepatocellular carcinoma, Diabetes

Core tip: IGF-1 promoted the growth and metastasis of the hepatocellular carcinoma via its ability to enhance cathepsin B (CTSB) expression. CTSB depletion protects against the tumor-promoting actions of IGF-1 in hepatocellular carcinoma (HCC) cells, as well tumor growth and metastasis both in vitro and in vivo. Our results showed that IGF-1 promotes HCC most likely by hindering CTSB degradation mediated by the ubiquitin-proteasome system (UPS). Proteasome activator 28 overexpression could not only restore IGF-1-inhibited UPS activity but also decrease IGF-1-induced CTSB accumulation. Our study demonstrates that targeting CTSB expression may contribute to therapeutic strategies for the treatment of cancers associated with diabetes.