ERBB4 acts as a suppressor in the development of hepatocellular carcinoma.
ERBB4, one member of the epidermal growth factor receptor (EGFR) family, plays a key role in physiological and pathological processes. Recently, we identified that ERBB4 played a protective role from chronic hepatitis B virus infection. However, the role of ERBB4 in hepatocellular carcinoma (HCC) is still unclear. Here, we explore the role of ERBB4 in the development of HCC using in vitro models, in vivo animal models and clinical samples of HCC. Liver-specific ERBB4 knockout alleles and full ERBB4 except heart knockout mice were used in this study. Liver inflammation and tumor models of mice were produced by carbon tetrachloride (CCl4) and diethylnitrosamine (DEN) administration, respectively. Commercial tissue arrays of 90 HCC patients with paired counterparts were used to evaluate the expression and the prognostic value of ERBB4. Genes altered in the setting of ERBB4 loss was studied by microarray analysis and further validated by real-time PCR. We have found that depletion of ERBB4 in mice leads to more severe injury and liver tumor formation and loss of ERBB4 contributes to the development of hepatocellular tumor. In clinic samples of HCC, ERBB4 is down-regulated and exhibit prognostic value of HCC patients. Mechanistically, loss of ERBB4 suppressed p53 expression by inhibiting the expression of the tumor suppressor tp53inp1. Our study uncovers ERBB4 as a suppressor in the development of HCC and implies an ERBB4-TP53INP1-P53 axis in HCC.
Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou 215123, People's Republic of China.
Yao
Y
Liu
Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China.
Liming
L
Song
Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou 215123, People's Republic of China.
Hengli
H
Ni
Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou 215123, People's Republic of China.
Lina
L
Sun
Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou 215123, People's Republic of China.
Weijuan
W
Jiao
Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China.
Lin
L
Chen
Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou 215123, People's Republic of China.
Qun
Q
Zhou
Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou 215123, People's Republic of China.
Tong
T
Shen
Department of Pathology, Second Affiliated Hospital of Soochow University, Suzhou 215004, People's Republic of China and.
Hongxia
H
Cui
Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, People's Republic of China.
Tianming
T
Gao
Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou 215123, People's Republic of China.|Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China.
Jianming
J
Li
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D056945:Hep G2 Cells; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011379:Prognosis; D066247:Receptor, ErbB-4 / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D025521:Tumor Suppressor Proteins; D066247:Receptor, ErbB-4