Seo-Gyu Park1, Mi-Jung Ji2, In-Hye Ham3,4, Yoon-Hee Shin1, Su-Min Lee1, Chang Hoon Lee5,6, Eunjung Kim7, Hoon Hur3,4,8, Hyun-Mee Park2, Jae-Young Kim9. 1. Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon, 34134, Republic of Korea. 2. Advanced Analysis and Data Center, Korea Institute of Science and Technology (KIST), Seoul, 02456, Republic of Korea. 3. Department of Surgery, Ajou University School of Medicine, Suwon, 16499, Republic of Korea. 4. Inflammaging Translational Research Cancer, Ajou University School of Medicine, Suwon, 16499, Republic of Korea. 5. Therapeutics and Biotechnology Division, Drug Discovery Platform Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea. 6. R and D center, SCBIO Co. Ltd, Daejeon, 34050, Republic of Korea. 7. Natural Product Informatics Center, Korea Institute of Science and Technology (KIST), Gangneung, 25451, Republic of Korea. 8. Department of Biomedical Science, Graduated School of Ajou University, Suwon, 16499, Republic of Korea. 9. Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon, 34134, Republic of Korea. jaeyoungkim@cnu.ac.kr.
Abstract
BACKGROUND: Cancer-associated fibroblasts (CAFs) are major components of the tumor microenvironment (TME). Hypoxic TME is known to promote tumor progression. However, how a hypoxic condition regulates CAFs remains elusive. METHODS: To investigate the underlying mechanism involved in the regulation of gastric cancer (GC) progression by hypoxic CAFs, we performed secretome profiling. Normoxic or hypoxic CAFs conditioned media (CM) were filter-concentrated and in-gel trypsin digested. Resulting peptides were analyzed with LC-MS/MS. RESULTS: We observed that CM derived from hypoxic CAFs could promote migration of a panel of GC cell lines (AGS, SNU668, SNU638). Mass spectrometry analysis of hypoxic or normoxic CAFs CM identified 1595 proteins, of which 19 proteins (10 upregulated and 9 downregulated) were differentially expressed in the hypoxic secretome. We focused on COL4A2, whose expression was significantly decreased in hypoxic CAFs in HIF-1α-independent manner. Silencing of COL4A2 expression in normoxic CAFs phenocopied the effect of hypoxic CAFs in promoting GC cell migration. CONCLUSIONS: The reduced expression of COL4A2 in a hypoxic environment might be associated with the tumor-promoting role of hypoxic CAFs in GC.
BACKGROUND: Cancer-associated fibroblasts (CAFs) are major components of the tumor microenvironment (TME). Hypoxic TME is known to promote tumor progression. However, how a hypoxic condition regulates CAFs remains elusive. METHODS: To investigate the underlying mechanism involved in the regulation of gastric cancer (GC) progression by hypoxic CAFs, we performed secretome profiling. Normoxic or hypoxic CAFs conditioned media (CM) were filter-concentrated and in-gel trypsin digested. Resulting peptides were analyzed with LC-MS/MS. RESULTS: We observed that CM derived from hypoxic CAFs could promote migration of a panel of GC cell lines (AGS, SNU668, SNU638). Mass spectrometry analysis of hypoxic or normoxic CAFs CM identified 1595 proteins, of which 19 proteins (10 upregulated and 9 downregulated) were differentially expressed in the hypoxic secretome. We focused on COL4A2, whose expression was significantly decreased in hypoxic CAFs in HIF-1α-independent manner. Silencing of COL4A2 expression in normoxic CAFs phenocopied the effect of hypoxic CAFs in promoting GC cell migration. CONCLUSIONS: The reduced expression of COL4A2 in a hypoxic environment might be associated with the tumor-promoting role of hypoxic CAFs in GC.
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