Hepatitis B virus X protein induces epithelial-mesenchymal transition by repressing E-cadherin expression via upregulation of E12/E47.
Previous reports have demonstrated that hepatitis B virus (HBV) X protein (HBx) represses E-cadherin expression to induce epithelial-mesenchymal transition (EMT), an essential component of cancer progression to more aggressive phenotypes characterized by tumour invasion, migration and metastasis; however, the underlying mechanism for this phenomenon is still unclear. In this study, we found that ectopic expression of HBx in human hepatocytes using overexpression and 1.2-mer WT HBV replicon systems upregulated levels of the transcriptional repressors E12 and E47, resulting in inactivation of the E-cadherin promoter, containing three E-box motifs, and subsequent repression of its expression. E12/E47 knockdown using a specific small interfering RNA almost completely abolished the potential of HBx to repress E-cadherin expression. HBx inhibited the ubiquitin-dependent proteasomal degradation of E12/E47 without affecting their expression at the transcriptional level. Upregulation of E12/E47 by HBx ultimately led to EMT in human hepatocytes, as demonstrated by morphological changes, altered protein levels of EMT markers, including E-cadherin, plakoglobin, fibronectin, vimentin and N-cadherin, and increased capacity for cell detachment and migration.
Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.
Soo
S
Shin Kim
Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.
Sujeong
S
Yeom
Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.
Juri
J
Kwak
Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.
Hyung-Jun
HJ
Ahn
Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.
Kyung
K
Lib Jang
D015820:Cadherins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D058750:Epithelial-Mesenchymal Transition; D005786:Gene Expression Regulation / Q000187:drug effects*; D006515:Hepatitis B virus / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D015534:Trans-Activators / Q000378:metabolism*; D058127:Transcription Factor 3 / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
D015820:Cadherins; D015534:Trans-Activators; D058127:Transcription Factor 3; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein