Hepatitis B virus X protein promotes hepatocellular carcinoma invasion and metastasis via upregulating thioredoxin interacting protein.

Abstract

Hepatitis B virus X protein (HBx), a multifunctional protein encoded by the X gene of the hepatitis B virus (HBV) is involved in the metastasis of HBV-associated hepatocellular carcinoma (HCC) through various pathways, including upregulating intracellular reactive oxygen species (ROS). Thioredoxin interacting protein (TXNIP) is a key mediator of intracellular ROS, but its function in HBx-mediated metastasis of HBV-associated HCC is elusive. In the present study, HBV-associated HCC tissues with or without metastasis and HepG2 cells were used to study the function of TXNIP in HBx-mediated metastasis of HBV-associated HCC. Initially, the expression levels of TXNIP and HBx in HBV-associated HCC tissues were detected by immunohistochemistry and reverse transcription-quantitative polymerase chain reaction. The results revealed that high expression of TXNIP may be an independent risk factor for metastasis of HBV-associated HCC, and the mRNA levels of TXNIP and HBx were positively associated. Secondly, the association between HBx and TXNIP was investigated using a HBx expression stable cell line, in which HBx expression was induced and controlled by doxycycline. The results demonstrated that HBx may upregulate TXNIP expression in HepG2 cells. Thirdly, the effects of TXNIP and HBx on HepG2 cell migration and invasion were studied by scratch and Matrigel invasion assays, respectively. The results demonstrated that TXNIP overexpression enhanced HepG2 cell migration and invasion. In addition, ectopic expression of HBx promoted HepG2 cell migration and invasion, and this effect may be attenuated by knockdown of TXNIP expression, which indicated that TXNIP may be involved in the process. In summary, the present results demonstrated that TXNIP may be involved in HBx-mediated metastasis of HBV-associated HCC.