title: Increase in L-type amino acid transporter 1 expression during cholangiocarcinogenesis caused by liver fluke infection and its prognostic significance.
abstract: L-type amino acid transporter 1 (LAT1) is highly expressed in various human cancers, including cholangiocarcinoma (CCA), the most common cancer in Northeast Thailand. Chronic inflammation and oxidative stress induced by liver fluke, Opisthorchis viverrini, infection has been recognized as the major cause of CCA in this area. We show here that an increased expression of LAT1 and its co-functional protein CD98 are found during carcinogenesis induced by Ov in hamster CCA tissues. We also demonstrate that oxidative stress induced by H2O2is time-dependent and dramatically activates LAT1 and CD98 expression in immortal cholangiocytes (MMNK1). In addition, H2O2treatment increased LAT1 and CD98 expression, as well as an activated form of AKT and mTOR in MMNK1 and CCA cell lines (KKU-M055 and KKU-M213). We also show that suppression of PI3K/AKT pathway activity with a dual PI3K/mTOR inhibitor, BEZ235, causes a reduction in LAT1 and CD98 expression in KKU-M055 and KKU-M213 in parallel with a reduction of activated AKT and mTOR. Interestingly, high expression of LAT1 in human CCA tissues is a significant prognostic factor for shorter survival. Taken together, our data show that LAT1 expression is significantly associated with CCA progression and cholangiocarcinogenesis induced by oxidative stress. Moreover, the expression of LAT1 and CD98 in CCA is possibly regulated by the PI3K/AKT signaling pathway.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Supak
authors.initials: S
authors.lastname: Yothaisong
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Nisana
authors.initials: N
authors.lastname: Namwat
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Puangrat
authors.initials: P
authors.lastname: Yongvanit
authors.affiliation: Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Narong
authors.initials: N
authors.lastname: Khuntikeo
authors.affiliation: Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Anucha
authors.initials: A
authors.lastname: Puapairoj
authors.affiliation: Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan.
authors.forename: Promsuk
authors.initials: P
authors.lastname: Jutabha
authors.affiliation: Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Anzai
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Wichittra
authors.initials: W
authors.lastname: Tassaneeyakul
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Panot
authors.initials: P
authors.lastname: Tangsucharit
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen 40002, Thailand. Electronic address: watloi@yahoo.com.
authors.forename: Watcharin
authors.initials: W
authors.lastname: Loilome
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001650:Bile Duct Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D002460:Cell Line; D018281:Cholangiocarcinoma / Q000175:diagnosis / Q000378:metabolism*; D006224:Cricetinae; D005260:Female; D027261:Fusion Regulatory Protein-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D008875:Middle Aged; D009889:Opisthorchiasis / Q000150:complications / Q000175:diagnosis / Q000378:metabolism*; D009891:Opisthorchis / Q000502:physiology*; D018384:Oxidative Stress; D011379:Prognosis; D046888:Tissue Array Analysis; D015854:Up-Regulation
chemical_list: D027261:Fusion Regulatory Protein-1; D027283:Large Neutral Amino Acid-Transporter 1
keywords: Cholangiocarcinoma; Inflammation; L-type amino acid transporter 1; Opisthorchis viverrini; Oxidative stress; PI3K/AKT signaling