title: Autophagy may occur at an early stage of cholangiocarcinogenesis via biliary intraepithelial neoplasia.
abstract: Similar to the pancreatic carcinoma sequence model, cholangiocarcinoma reportedly follows a stepwise carcinogenesis process via the precursor lesion biliary intraepithelial neoplasia (BilIN). Given that autophagy plays an important role in the occurrence and development of carcinomas, we examined the involvement of autophagy in multistep cholangiocarcinogenesis. Thirty-six patients with hepatolithiasis associated with BilIN and/or cholangiocarcinoma, 7 with intrahepatic cholangiocarcinoma, 8 with intraductal papillary neoplasm of the bile duct (IPNB), and 6 with control livers were surveyed. Their lesions were categorized as follows: invasive carcinoma (n = 16), IPNB (n = 8), BIlN-3 (n = 16), BilIN-1/2 (n = 40), nonneoplastic large bile duct (n = 55), and peribiliary gland (n = 55). We examined the immunohistochemical expression of autophagy-related proteins, microtubule-associated proteins light chain 3β (LC3), beclin-1, and p62/sequestosome-1 (p62), as well as tumor suppressor gene product p53. The extent of expression was semiquantitatively assessed. The status of KRAS mutations at codons 12 and 13 was examined in selected cases of BilIN-1/2. The expression of LC3 (cytoplasmic), beclin-1 (cytoplasmic), and p62 (cytoplasmic and nuclear) was significantly higher in BilIN-1/2, BilIN-3, IPNB, and invasive carcinoma than in large bile duct and peribiliary gland (P < .01). KRAS mutation was detected in 6 (40%) of 15 BilIN-1/2 lesions, and there was no correlation between the status of KRAS mutation and the expression of autophagy-related proteins. In conclusion, this study is the first to disclose that the expression of autophagy-related proteins, LC3, beclin-1, and p62, was increased at an early stage of multistep cholangiocarcinogenesis in hepatolithiasis. Autophagy, probably deregulated autophagy, may be related to the occurrence and development of cholangiocarcinoma.
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Nitta
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan; Department of Pathology, Shizuoka Cancer Center, Shizuoka 411-8777, Japan.
authors.forename: Yasuni
authors.initials: Y
authors.lastname: Nakanuma
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071186:Beclin-1; D001650:Bile Duct Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology*; D018281:Cholangiocarcinoma / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009367:Neoplasm Staging; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D016601:RNA-Binding Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C117307:KRAS protein, human; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C118585:P62 protein, human; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: Autophagy; Beclin-1; Biliary intraepithelial neoplasia (BilIN); Intrahepatic cholangiocarcinoma; KRAS; Microtubule-associated proteins light chain 3 beta (LC3); p62/sequestosome-1