title: Hypoxia enhances cholangiocarcinoma invasion through activation of hepatocyte growth factor receptor and the extracellular signal‑regulated kinase signaling pathway.
abstract: Hypoxia is associated with tumor progression and poor prognosis in several cancer types. The present study aimed to examine the contribution of hypoxia (1% O2) to cancer progression in a cholangiocarcinoma cell line, RMCCA‑1. The molecular basis of the hypoxic response pathway was investigated. The results showed that hypoxia significantly accelerated cancer cell proliferation and enhanced cell invasion (P<0.05). By using receptor tyrosine kinase and intracellular signaling antibody array kits, an increased phosphorylation/activation of a number of signaling molecules, particularly hepatocyte growth factor receptor (Met) and extracellular signal‑regulated kinase (ERK) 1/2, was identified. Inhibition of Met and ERK by small hairpin RNA and U0126, respectively, significantly inhibited hypoxia‑induced the invasive potential of RMCCA‑1 cells (P<0.05). However, according to immunohistochemical analysis, hypoxia‑inducible factor‑1α expression was not correlated with cancer staging or tumor differentiation in 44 samples of cholangicarcinoma cases. The findings of the present study emphasized the importance of Met/ERK pathway activation as a key molecular event that may be responsible for a more invasive phenotype in hypoxic tumors and suggest Met as a potential target for the treatment of cholangiocarcinoma.
authors.affiliation: Department of Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Thitinee
authors.initials: T
authors.lastname: Vanichapol
authors.affiliation: Department of Surgery, Rajavithi Hospital, Bangkok 10400, Thailand.
authors.forename: Kawin
authors.initials: K
authors.lastname: Leelawat
authors.affiliation: Department of Pediatrics, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Suradej
authors.initials: S
authors.lastname: Hongeng
mesh_terms: D001650:Bile Duct Neoplasms / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020935:MAP Kinase Signaling System; D009361:Neoplasm Invasiveness / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019859:Proto-Oncogene Proteins c-met; D048049:Extracellular Signal-Regulated MAP Kinases