The HBx–CTTN interaction promotes cell proliferation and migration of hepatocellular carcinoma via CREB1

Yajun Li, Yongming Fu, Xingwang Hu, Lunquan Sun, Daolin Tang, Ning Li, Fang Peng, Xue gong Fan

Research output: Contribution to journalArticle

Abstract

Hepatitis B virus-encoded X protein (HBx) acts as a tumor promoter during hepatocellular carcinoma (HCC) development, probably by regulating the expression of host proteins through protein–protein interaction. A proteomics approach was used to identify HBx-interacting proteins involved in HBx-induced hepatocarcinogenesis. We validated the proteomics findings by co-immunoprecipitation and confocal microscopy. We performed cell proliferation, migration assays and cell cycle analyses in HCC cells. Finally, we confirmed the clinical significance of our findings in samples from patients. We found that cortactin (CTTN) is a novel HBx-interacting protein, and HBx regulates the expression of CTTN in the HCC cell lines MHCC-LM3 and HepG2. Mechanistically, by upregulating the expression of cAMP response element-binding protein (CREB1) and its downstream targets, such as cyclin D1 and MMP-9, the effects of the HBx-CTTN interaction on the enhancement of cellular proliferation and migration were maintained by inhibiting cell cycle arrest. In addition, we demonstrated that the levels of CTTN and CREB1 were closely correlated in clinical samples from HBV-infected patients with HCC. Overall, our data suggests that HBx contributes to cell migration and proliferation of HCC cells by interacting with CTTN and regulating the expression of CTTN and CREB1. Therefore, the HBx/CTTN/CREB1 axis is a potential novel therapeutic target in HCC.

Original languageEnglish (US)
Article number405
JournalCell Death and Disease
Volume10
Issue number6
DOIs
StatePublished - Jun 1 2019

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Cortactin
Cell Movement
Hepatocellular Carcinoma
Cell Proliferation
Proteomics
Cell Migration Assays
Cyclic AMP Response Element-Binding Protein
Proteins
Cyclin D1
Cell Cycle Checkpoints
Matrix Metalloproteinases
Immunoprecipitation
Confocal Microscopy
Carcinogens
Cell Cycle
Cell Line

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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The HBx–CTTN interaction promotes cell proliferation and migration of hepatocellular carcinoma via CREB1. / Li, Yajun; Fu, Yongming; Hu, Xingwang; Sun, Lunquan; Tang, Daolin; Li, Ning; Peng, Fang; Fan, Xue gong.

In: Cell Death and Disease, Vol. 10, No. 6, 405, 01.06.2019.

Research output: Contribution to journalArticle

Li, Yajun ; Fu, Yongming ; Hu, Xingwang ; Sun, Lunquan ; Tang, Daolin ; Li, Ning ; Peng, Fang ; Fan, Xue gong. / The HBx–CTTN interaction promotes cell proliferation and migration of hepatocellular carcinoma via CREB1. In: Cell Death and Disease. 2019 ; Vol. 10, No. 6.
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abstract = "Hepatitis B virus-encoded X protein (HBx) acts as a tumor promoter during hepatocellular carcinoma (HCC) development, probably by regulating the expression of host proteins through protein–protein interaction. A proteomics approach was used to identify HBx-interacting proteins involved in HBx-induced hepatocarcinogenesis. We validated the proteomics findings by co-immunoprecipitation and confocal microscopy. We performed cell proliferation, migration assays and cell cycle analyses in HCC cells. Finally, we confirmed the clinical significance of our findings in samples from patients. We found that cortactin (CTTN) is a novel HBx-interacting protein, and HBx regulates the expression of CTTN in the HCC cell lines MHCC-LM3 and HepG2. Mechanistically, by upregulating the expression of cAMP response element-binding protein (CREB1) and its downstream targets, such as cyclin D1 and MMP-9, the effects of the HBx-CTTN interaction on the enhancement of cellular proliferation and migration were maintained by inhibiting cell cycle arrest. In addition, we demonstrated that the levels of CTTN and CREB1 were closely correlated in clinical samples from HBV-infected patients with HCC. Overall, our data suggests that HBx contributes to cell migration and proliferation of HCC cells by interacting with CTTN and regulating the expression of CTTN and CREB1. Therefore, the HBx/CTTN/CREB1 axis is a potential novel therapeutic target in HCC.",
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