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The oncoprotein HBXIP facilitates metastasis of hepatocellular carcinoma cells by activation of MMP15 expression

Authors Zheng S, Wu H, Wang F, Lv J, Lu J, Fang Q, Wang F, Lu Y, Zhang S, Xu Y, Bao Q, Xie C, Yin Z

Received 19 December 2018

Accepted for publication 21 March 2019

Published 16 May 2019 Volume 2019:11 Pages 4529—4540

DOI https://doi.org/10.2147/CMAR.S198783

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 3

Editor who approved publication: Dr Kenan Onel


Sen Zheng,1,* Huita Wu,2,* Fei Wang,1,* Jie Lv,1 Jing Lu,1 Qinliang Fang,1 Fuqiang Wang,1 Yuyan Lu,1 Sheng Zhang,1 Yaping Xu,3 Qing Bao,1 Chengrong Xie,1 Zhenyu Yin1

1Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen 361004, Fujian, People’s Republic of China; 2Department of Oncology, Zhongshan Hospital, Xiamen University, Xiamen 361004, Fujian, People’s Republic of China; 3Key laboratory of functional and clinical translational medicine, Xiamen Medical College, Xiamen 361004, Fujian, People’s Republic of China

*These authors contributed equally to this work

Background:
Due to the high recurrence and metastasis rate, the clinical outcomes of patients with hepatocellular carcinoma (HCC) are still unsatisfactory. Hepatitis B virus X-interacting protein (HBXIP) has been reported to play crucial roles in carcinogenesis.
Purpose: We aimed to reveal the functional significance and underlying mechanism of HBXIP in HCC metastasis.Methods: Cell transwell assay, in vivo metastasis model, real-time PCR, western blot analysis, luciferase reporter and chromatin immunoprecipitation assays were applied.
Results: Here, we detected the HBXIP expression level and determined its clinical significance in HCC. We found that HBXIP was significantly upregulated in HCC tissues, and correlated with vascular invasion, tumor metastasis and worse prognosis of HCC patients. HBXIP enhanced cell migration and invasion in vitro, and promoted the metastasis of HCC in vivo. Furthermore, we confirmed that HBXIP increased MMP15 expression through association with proto-oncogene c-myc. Depletion of c-myc abolished HBXIP-mediated MMP-15 upregulation. We also observed a positive correlation between HBXIP and MMP15 expression in HCC tissues.
Conclusion: Our results establish a novel function for HBXIP-MMP15 regulation in HCC metastasis and suggest its candidacy as a new prognostic biomarker and therapeutic target for HCC metastasis.

Keywords: c-myc, MMP15, HBXIP, metastasis

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