Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/79229
Title: Hepatitis transactivator protein X promotes extracellular matrix modification through HIF/LOX pathway in liver cancer
Authors: Tse, APW
Sze, KMF
Shea, QTK 
Chiu, EYT
Tsang, FHC
Chiu, DKC
Zhang, MS
Lee, D
Xu, IMJ
Chan, CYK
Koh, HY
Wong, CM
Zheng, YP 
Ng, IOL
Wong, CCL
Issue Date: 2018
Publisher: Nature Publishing Group
Source: Oncogenesis, 25 May 2018, v. 7, 44, p. 1-12 How to cite?
Journal: Oncogenesis 
Abstract: Hepatocellular carcinoma (HCC), accounting for 90% of primary liver cancer, is a lethal malignancy that is tightly associated with chronic hepatitis B virus (HBV) infection. HBV encodes a viral onco-protein, transactivator protein X (HBx), which interacts with proteins of hepatocytes to promote oncogenesis. Our current study focused on the interaction of HBx with a transcription factor, hypoxia-inducible factor-1 alpha (HIF-1 alpha), which is stabilized by low O-2 condition (hypoxia) and is found to be frequently overexpressed in HCC intra-tumorally due to poor blood perfusion. Here, we showed that overexpression of HBx by tetracycline-inducible systems further stabilized HIF-1 alpha under hypoxia in HBV-negative HCC cell lines. Reversely, knockdown of HBx reduced HIF-1 alpha protein stabilization under hypoxia in HBV-positive HCC cell lines. More intriguingly, overexpression of HBx elevated the mRNA and protein expression of a family of HIF-1 alpha target genes, the lysyl oxidase (LOX) family in HCC. The LOX family members function to cross-link collagen in the extracellular matrix (ECM) to promote cancer progression and metastasis. By analyzing the collagens under scanning electron microscope, we found that collagen fibers were significantly smaller in size when incubated with conditioned medium from HBx knockdown HCC cells as compared to control HCC cells in vitro. Transwell invasion assay further revealed that less cells were able to invade through the matrigel which was pre-treated with conditioned medium from HBx knockdown HCC cells as compared to control HCC cells. Orthotopic and subcutaneous HCC models further showed that knockdown of HBx in HCC cells reduced collagen crosslinking and stiffness in vivo and repressed HCC growth and metastasis. Taken together, our in vitro and in vivo studies showed the HBx remodeled the ECM through HIF-1 alpha/LOX pathway to promote HCC metastasis.
URI: http://hdl.handle.net/10397/79229
EISSN: 2157-9024
DOI: 10.1038/s41389-018-0052-8
Rights: © The Author(s) 2018
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any mediumor format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changesweremade. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
The following publication Tse, A. P. -., Sze, K. M. -., Shea, Q. T. -., Chiu, E. Y. -., Tsang, F. H. -., Chiu, D. K. -., . . . Wong, C. C. -. (2018). Hepatitis transactivator protein X promotes extracellular matrix modification through HIF/LOX pathway in liver cancer. Oncogenesis, 7, 44, 1-12 is available at https://doi.org/10.1038/s41389-018-0052-8
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