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

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-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.

Intermittent Hypoxia Alleviates β-Aminopropionitrile Monofumarate Induced Thoracic Aortic Dissection in C57BL/6 Mice

“…The increase in HIF-1a by IH might not resist the inhibition of LOX, but according to existing studies IH could increase HIF-1a and HIF-1a promotes the expression of LOX. 20 The IH-HIF-1aeLOX pathway might have the effect of resisting the decrease in LOX. Other possible pathways involved in the protection of IH on TAD need further study.…”

The role of collagen in cancer: from bench to bedside

“…Other substances, such as hepatitis transactivator protein X in liver cancer [108], LKB1 via COLIV and β1 integrin in lung cancer [109], and HIF1α-dependent PLOD2 in primary sarcomas and pulmonary metastasis [110], participate with collagen in the HIF/LOX pathway. Hypoxia increased the expression of procollagenlysine as collagen crosslinker to further enhance collagen fiber size and thus promote cancer metastasis [111].…”

Microbial Biofilms: Human T-cell Leukemia Virus Type 1 First in Line for Viral Biofilm but Far Behind Bacterial Biofilms

“…It can also influence the process of carcinogenesis. For instance, Hepatitis B virus (HBV) encodes a viral onco-protein, transactivator protein X, involved in the ECM remodeling through the HIF-1α/LOX pathway, which is shown to promote hepatocellular carcinoma metastasis ( Tse et al, 2018 ). After productive infection, modulation of the ECM can also enhance viral transmission through cell-to-cell contact.…”