title: Complex Behavior of ALDH1A1 and IGFBP1 in Liver Metastasis from a Colorectal Cancer.
abstract: Using our data set (GSE50760) previously established by RNA sequencing, the present study aimed to identify upregulated genes associated with colorectal cancer (CRC) liver metastasis (CLM) and verify their biological behavior. The potential roles of candidate genes in tumors were assessed using cell proliferation and invasion assays. Tissue samples were collected from 18 CRC patients with synchronous CLM and two CRC cell lines (SW480 and SW620) were used for transfection and cloning. The roles of the genes identified in CLM were verified using immunohistochemistry in 48 nude mice after intrasplenic transplantation of CRC cells. mRNA and protein expression was determined by quantitative real-time reverse transcription polymerase chain reaction and western blot, respectively. Nine genes were initially selected according to the relevance of their molecular function and biological process and, finally, ALDH1A1 and IGFBP1 were chosen based on differential mRNA expression and a positive correlation with protein expression. The overexpression of ALDH1A1 and IGFBP1 significantly and time-dependently decreased cell proliferation (p ≤ 0.001-0.003) and suppressed invasiveness by ≥3-fold over control cells (p < 0.001) in the SW480 cell line, whereas they had a slight effect on reducing SW620 cell proliferation. The protein expression levels of E-cadherin, N-cadherin, claudin-1, and vimentin were significantly higher in CLM than in primary tumor tissues (p < 0.05). However, the cadherin switch, namely, N-cadherin overexpression with reduced E-cadherin expression, was not observed in CLM tissues and transfected CRC cells. Irrespective of reduced proliferation and invasion found on in vitro cell assays, persistent overexpression of β-catenin, vimentin, and ZO-1 in IGFBP1-overexpressing SW480 cells possibly contributed to CLM development in mice implanted with IGFBP1-overexpressing SW480 cells (CLM occurrences: SW480/IGFBP1-transfected mice vs. SW480/vector- and SW480/ALDH1A1-transfected mice, 4/8 vs. 0/10, p = 0.023). In conclusion, ALDH1A1 and IGFBP1 are differentially overexpressed in CLM and may play a dual role, functioning as both tumor suppressors and metastasis promoters in CRC.
authors.affiliation: Department of Surgery, University of Ulsan College of Medicine, Seoul, Korea.|Institute of Innovative Cancer Research, Asan Medical Center, Seoul, Korea.
authors.forename: Jin Cheon
authors.initials: JC
authors.lastname: Kim
authors.affiliation: Department of Surgery, University of Ulsan College of Medicine, Seoul, Korea.|Institute of Innovative Cancer Research, Asan Medical Center, Seoul, Korea.
authors.forename: Ye Jin
authors.initials: YJ
authors.lastname: Ha
authors.affiliation: Department of Surgery, University of Ulsan College of Medicine, Seoul, Korea.|Institute of Innovative Cancer Research, Asan Medical Center, Seoul, Korea.
authors.forename: Ka Hee
authors.initials: KH
authors.lastname: Tak
authors.affiliation: Department of Surgery, University of Ulsan College of Medicine, Seoul, Korea.|Institute of Innovative Cancer Research, Asan Medical Center, Seoul, Korea.
authors.forename: Seon Ae
authors.initials: SA
authors.lastname: Roh
authors.affiliation: Department of Surgery, University of Ulsan College of Medicine, Seoul, Korea.|Institute of Innovative Cancer Research, Asan Medical Center, Seoul, Korea.
authors.forename: Chan Wook
authors.initials: CW
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of Ulsan College of Medicine, Seoul, Korea.|Institute of Innovative Cancer Research, Asan Medical Center, Seoul, Korea.
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kim
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Korea.
authors.forename: Seon-Kyu
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Korea.
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Institute of Innovative Cancer Research, Asan Medical Center, Seoul, Korea.|Graduate School of East-West Medical Science, Kyung Hee University, Gyeonggi-do, Korea.
authors.forename: Dong-Hyung
authors.initials: DH
authors.lastname: Cho
authors.affiliation: Institute of Innovative Cancer Research, Asan Medical Center, Seoul, Korea.|Medical Genomics Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Korea.
authors.forename: Yong Sung
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics*; D008113:Liver Neoplasms / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050697:Retinal Dehydrogenase
chemical_list: C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase