title: Expression and activation of EGFR and STAT3 during the multistage carcinogenesis of intrahepatic cholangiocarcinoma induced by 3'-methyl-4 dimethylaminoazobenzene in rats.
abstract: The purpose of this study was to investigate whether the epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription-3 (STAT3) signal pathway contributes to the carcinogenesis of intrahepatic cholangiocarcinoma (ICC) induced by 3'-methyl-4 dimethylaminoazobenzene (3'Me-DAB) in rats. EGFR, TGFα, STAT3 and p-STAT3 in different stages of carcinogenesis were detected by immunohistochemistry (IHC). In situ hybridization (ISH) was applied to investigate the expression of STAT3 mRNA. Oval cells were verified by the immunohistochemical staining of alpha-fetoprotein (AFP), CD133 and epithelial cell adhesion molecules (EpCAM). Sequential development of necrosis, oval cell proliferation, cholangiofibrosis (CF) and ICC was observed in the liver of rats administered 3'Me-DAB. Oval cells showed positive expression of AFP, CD133 and EpCAM. The expression of EGFR was significantly higher in the ICC than in oval cells, CF or normal bile ducts (p<0.05), but there was no difference in EGFR expression between the other groups. The highest expression of p-STAT3 and TGFα was observed in CF. The expression of these two molecules in the ICC and oval cells was significantly higher than in normal bile ducts (p<0.05). Elevation of STAT3 mRNA was detected during carcinogenesis as shown by ISH, strong intensity was observed in the ICC and moderate intensity was observed in oval cells and CF. These observations suggest that the EGFR and STAT3 signal pathway contributes to the carcinogenesis of ICC. High activity of STAT3 during the carcinogenesis of ICC may be the result of high activity of EGFR triggered by TGFα.
authors.affiliation: Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian 116044, PR China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Forensic Medicine, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Lianhong
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian 116044, PR China.
authors.forename: Xingwu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pathology and Forensic Medicine, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Histology and Embryology, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Jinyao
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, PR China.
authors.forename: Shilun
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Pathology and Forensic Medicine, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Xiaotang
authors.initials: X
authors.lastname: Yu
keywords: 3’-methyl-4 dimethylaminoazobenzene; carcinogenesis; epidermal growth factor receptor; intrahepatic cholangiocarcinoma; oval cell; signal transducer and activator of transcription-3