title: Characterization of EGFR family gene aberrations in cholangiocarcinoma.
abstract: Cholangiocarcinoma (CCA) is a highly lethal malignancy of the biliary tract with very few treatment options. Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER2) have been considered as potential therapeutic targets in CCA. In the present study, we attempted to clarify the clinicopathological significance of all EGFR family members, EGFR, HER2, HER3 and HER4, across the full spectrum of CCAs. Immunohistochemistry and FISH were performed to validate expressions and genetic aberrations of these molecules retrospectively in 175 CCA patients. EGFR, HER3 and HER4 were overexpressed in 20 (30.8%), 8 (12.3%) and 41 (63.1%) of the 65 intrahepatic cholangiocarcinomas (IHCCs), and in 23 (20.9%), 13 (11.8%) and 62 (56.4%) of the 110 extrahepatic cholangiocarcinomas (EHCCs), respectively. Overexpression of HER2 was exclusively identified in EHCCs, among which the rate was 4.5% (5/110). A significant association was identified between EGFR amplification and EGFR overexpression (P=0.002). Similarly, HER2 amplification was strongly associated with HER2 overexpression (P<0.001). Multivariate analysis suggested that EGFR overexpression is an independent prognostic factor in IHCC, but not in EHCC cases [HR (95% CI): 3.689 (1.253-10.587), P=0.018]. Notably, for the first time, we demonstrated HER4 expression is a prognostic factor in EGFR-negative IHCC patients. In vitro data further suggested a tumor-suppressor role of HER4 in CCA. siRNA knockdown of HER4 significantly increased RBE cell migration and invasion. By contrast, HER4 overexpression decreased proliferation of HuCCT-1 cells and their migratory and invasive capacity. In summary, our results revealed expression of the EGFR family members in CCA development and progression. CCAs differentially express HER2 protein based on tumor location. HER4 expression status allows stratification of CCA patients into different survival categories.
authors.affiliation: Department of Pathology, Shandong University Medical School, Jinan, Shandong, P.R. China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of General Surgery, Yishui Central Hospital, Linyi, Shandong, P.R. China.
authors.forename: Weishan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pathology, Shandong University Medical School, Jinan, Shandong, P.R. China.
authors.forename: Chunni
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pathology, Shandong University Medical School, Jinan, Shandong, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, Shandong University Medical School, Jinan, Shandong, P.R. China.
authors.forename: Muyi
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Pathology, Shandong University Medical School, Jinan, Shandong, P.R. China.
authors.forename: Mei
authors.initials: M
authors.lastname: Qi
authors.affiliation: Department of Pathology, Shandong University Medical School, Jinan, Shandong, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Statistics, Shandong University School of Public Health, Jinan, Shandong, P.R. China.
authors.forename: Xiubin
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Pathology, Shandong University Medical School, Jinan, Shandong, P.R. China.
authors.forename: Zhiyan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pathology, Shandong University Qilu Hospital, Jinan, Shandong, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Shandong University Qilu Hospital, Jinan, Shandong, P.R. China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Qin
authors.affiliation: Department of Pathology, Shandong University Medical School, Jinan, Shandong, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Han
mesh_terms: D000368:Aged; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis
chemical_list: D066246:ErbB Receptors