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Oncogenesis v.7 no.5, 2018년, pp.44 -    SCIE
본 등재정보는 저널의 등재정보를 참고하여 보여주는 베타서비스로 정확한 논문의 등재여부는 등재기관에 확인하시기 바랍니다.

Hepatitis transactivator protein X promotes extracellular matrix modification through HIF/LOX pathway in liver cancer

Tse, Aki Pui-Wah    (Department of Pathology, The University of Hong Kong, Hong Kong, China   ); Sze, Karen Man-Fong    (Department of Pathology, The University of Hong Kong, Hong Kong, China   ); Shea, Queenie Tsung-Kwan    (Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong, China   ); Chiu, Elley Yung-Tuen    (Department of Pathology, The University of Hong Kong, Hong Kong, China   ); Tsang, Felice Ho-Ching    (Department of Pathology, The University of Hong Kong, Hong Kong, China   ); Chiu, David Kung-Chun    (Department of Pathology, The University of Hong Kong, Hong Kong, China   ); Zhang, Misty Shuo    (Department of Pathology, The University of Hong Kong, Hong Kong, China   ); Lee, Derek    (Department of Pathology, The University of Hong Kong, Hong Kong, China   ); Xu, Iris Ming-Jing    (Department of Pathology, The University of Hong Kong, Hong Kong, China   ); Chan, Cerise Yuen-Ki    (Department of Pathology, The University of Hong Kong, Hong Kong, China   ); Koh, Hui-Yu    (Department of Pathology, The University of Hong Kong, Hong Kong, China   ); Wong, Chun-Ming    (Department of Pathology, The University of Hong Kong, Hong Kong, China   ); Zheng, Yong-Ping    (Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong, China   ); Ng, Irene Oi-Lin    (Departm  ); Wong, Carmen Chak-Lui  
  • 초록  

    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 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-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.


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