title: Chronic lung injury by constitutive expression of activation-induced cytidine deaminase leads to focal mucous cell metaplasia and cancer.
abstract: Activation-induced cytidine deaminase (AID) is an enzyme required for antibody diversification, and it causes DNA mutations and strand breaks. Constitutive AID expression in mice invariably caused lung lesions morphologically similar to human atypical adenomatous hyperplasia (AAH), which can be a precursor of bronchioloalveolar carcinoma. Similar to AAH, mouse AAH-like lesion (MALL) exhibited signs of alveolar differentiation, judging from the expression of alveolar type II (AT2) cell marker surfactant protein C (SP-C). However, electron microscopy indicated that MALL, which possessed certain features of a mucous cell, is distinct from an AAH or AT2 cell. Although MALL developed in all individuals within 30 weeks after birth, lung tumors occurred in only 10%; this suggests that the vast majority of MALLs fail to grow into visible tumors. MALL expressed several recently described markers of lung alveolar regeneration such as p63, keratin 5, keratin 14, leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), and Lgr6. Increased cell death was observed in the lungs of AID transgenic mice compared with wild-type mice. Based on these observations, we speculate that MALL is a regenerating tissue compensating for cellular loss caused by AID cytotoxicity. AID expression in such regenerating tissue should predispose cells to malignant transformation via its mutagenic activity.
authors: Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan; Department of Thoracic Surgery, Nagahama City Hospital, Nagahama, Japan.
authors: Jiro
authors: J
authors: Kitamura
authors: Shiga Medical Center Research Institute, Moriyama, Japan.
authors: Munehiro
authors: M
authors: Uemura
authors: Shiga Medical Center Research Institute, Moriyama, Japan.
authors: Mafumi
authors: M
authors: Kurozumi
authors: Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan.
authors: Makoto
authors: M
authors: Sonobe
authors: Shiga Medical Center Research Institute, Moriyama, Japan.
authors: Toshiaki
authors: T
authors: Manabe
authors: Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Hiroshi
authors: H
authors: Hiai
authors: Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan.
authors: Hiroshi
authors: H
authors: Date
authors: Shiga Medical Center Research Institute, Moriyama, Japan.
authors: Kazuo
authors: K
authors: Kinoshita
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003564:Cytidine Deaminase / Q000096:biosynthesis* / Q000235:genetics; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D055370:Lung Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008679:Metaplasia / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D020545:Respiratory Mucosa / Q000201:enzymology* / Q000473:pathology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase