Hepatitis transactivator protein X promotes extracellular matrix modification through HIF/LOX pathway in liver cancer
| Autor: | Irene Oi-Lin Ng, Misty Shuo Zhang, Derek Lee, Carmen Chak-Lui Wong, Yongping Zheng, Aki Pui-Wah Tse, David Kung-Chun Chiu, Karen Man Fong Sze, Felice Ho-Ching Tsang, Queenie Tsung Kwan Shea, Cerise Yuen Ki Chan, Hui Yu Koh, Iris Ming-Jing Xu, Chun-Ming Wong, Elley Yung Tuen Chiu |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Matrigel Gene knockdown Chemistry viruses Lysyl oxidase lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease_cause lcsh:RC254-282 Article digestive system diseases Extracellular matrix 03 medical and health sciences HBx 030104 developmental biology 0302 clinical medicine Cell culture 030220 oncology & carcinogenesis medicine Cancer research Protein stabilization Carcinogenesis neoplasms Molecular Biology |
| Zdroj: | Oncogenesis Oncogenesis, Vol 7, Iss 5, Pp 1-12 (2018) |
| ISSN: | 2157-9024 |
| DOI: | 10.1038/s41389-018-0052-8 |
| Popis: | 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-1α (HIF-1α), which is stabilized by low O2 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-1α under hypoxia in HBV-negative HCC cell lines. Reversely, knockdown of HBx reduced HIF-1α 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-1α 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-1α/LOX pathway to promote HCC metastasis. |
| Databáze: | OpenAIRE |
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