title: Fibulin-3 negatively regulates ALDH1 via c-MET suppression and increases γ-radiation-induced sensitivity in some pancreatic cancer cell lines.
abstract: Fibulin-3 (FBLN-3) has been postulated to be either a tumor suppressor or promoter depending on the cell type, and hypermethylation of the FBLN-3 promoter is often associated with human disease, especially cancer. We report that the promoter region of the FBLN-3 was significantly methylated (>95%) in some pancreatic cancer cell lines and thus FBLN-3 was poorly expressed in pancreatic cancer cell lines such as AsPC-1 and MiaPaCa-2. FBLN-3 overexpression significantly down-regulated the cellular level of c-MET and inhibited hepatocyte growth factor-induced c-MET activation, which were closely associated with γ-radiation resistance of cancer cells. Moreover, we also showed that c-MET suppression or inactivation decreased the cellular level of ALDH1 isozymes (ALDH1A1 or ALDH1A3), which serve as cancer stem cell markers, and subsequently induced inhibition of cell growth in pancreatic cancer cells. Therefore, forced overexpression of FBLN-3 sensitized cells to cytotoxic agents such as γ-radiation and strongly inhibited the stemness and epithelial to mesenchymal transition (EMT) property of pancreatic cancer cells. On the other hand, if FBLN3 was suppressed in FBLN-3-expressing BxPC3 cells, the results were opposite. This study provides the first demonstration that the FBLN-3/c-MET/ALDH1 axis in pancreatic cancer cells partially modulates stemness and EMT as well as sensitization of cells to the detrimental effects of γ-radiation.
authors.affiliation: Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 989-111 Daedeok-daero, Yuseong-gu, Daejeon 305-353, Republic of Korea; Department of Radiation Biotechnology and Applied Radioisotope, Korea University of Science and Technology (UST), 989-111 Daedeok-daero, Yusong-gu, Daejeon 305-353, Republic of Korea. Electronic address: igkim@kaeri.re.kr.
authors.forename: In-Gyu
authors.initials: IG
authors.lastname: Kim
authors.affiliation: Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 989-111 Daedeok-daero, Yuseong-gu, Daejeon 305-353, Republic of Korea; Department of Radiation Biotechnology and Applied Radioisotope, Korea University of Science and Technology (UST), 989-111 Daedeok-daero, Yusong-gu, Daejeon 305-353, Republic of Korea.
authors.forename: Jae-Ha
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 989-111 Daedeok-daero, Yuseong-gu, Daejeon 305-353, Republic of Korea.
authors.forename: Seo-Yoen
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 989-111 Daedeok-daero, Yuseong-gu, Daejeon 305-353, Republic of Korea.
authors.forename: Jeong-Yul
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Epigenomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Republic of Korea.
authors.forename: Eun-Wie
authors.initials: EW
authors.lastname: Cho
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000595:Amino Acid Sequence; D001483:Base Sequence; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000528:radiation effects; D019175:DNA Methylation / Q000528:radiation effects; D058750:Epithelial-Mesenchymal Transition / Q000528:radiation effects; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D010179:Pancreas / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D011401:Promoter Regions, Genetic / Q000528:radiation effects; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000235:genetics* / Q000378:metabolism
chemical_list: C119630:EFEMP1 protein, human; D016326:Extracellular Matrix Proteins; D007527:Isoenzymes; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: ALDH; Cancer stem cell; Fibulin-3; c-MET