{"corpus_id":207754630,"paper_sha":null,"doi":"10.1158/0008-5472.CAN-07-1905","arxiv_id":null,"pmid":17942915,"pmcid":null,"mag_id":2109767417,"dblp_id":null,"acl_id":null,"title":"Loss of hepatocyte growth factor/c-Met signaling pathway accelerates early stages of N-nitrosodiethylamine induced hepatocarcinogenesis.","year":2007,"publication_date":"2007-10-15","venue":"Cancer Research","journal":{"name":"Cancer research","pages":"\n          9844-51\n        ","volume":"67 20"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article","Research Support, N.I.H., Intramural"],"s2_fields_of_study":["Biology","Medicine"],"reference_count":53,"citation_count":112,"influential_citation_count":1,"is_open_access":true,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":[{"d":"Acetylcysteine","mj":false,"qs":[{"q":"pharmacology","mj":false,"ui":"Q000494"}],"ui":"D000111"},{"d":"Animals","mj":false,"ui":"D000818"},{"d":"Antioxidants","mj":false,"qs":[{"q":"pharmacology","mj":false,"ui":"Q000494"}],"ui":"D000975"},{"d":"Cocarcinogenesis","mj":false,"ui":"D003043"},{"d":"Diethylnitrosamine","mj":false,"ui":"D004052"},{"d":"Gene Expression Regulation, Neoplastic","mj":false,"ui":"D015972"},{"d":"Hepatocyte Growth Factor","mj":false,"qs":[{"q":"deficiency","mj":true,"ui":"Q000172"},{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D017228"},{"d":"Liver","mj":false,"qs":[{"q":"drug effects","mj":false,"ui":"Q000187"},{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D008099"},{"d":"Liver Neoplasms, Experimental","mj":false,"qs":[{"q":"chemically induced","mj":true,"ui":"Q000139"},{"q":"genetics","mj":false,"ui":"Q000235"},{"q":"metabolism","mj":true,"ui":"Q000378"},{"q":"pathology","mj":false,"ui":"Q000473"}],"ui":"D008114"},{"d":"Mice","mj":false,"ui":"D051379"},{"d":"Mice, Knockout","mj":false,"ui":"D018345"},{"d":"Oxidative Stress","mj":false,"ui":"D018384"},{"d":"Proto-Oncogene Proteins c-met","mj":false,"qs":[{"q":"deficiency","mj":true,"ui":"Q000172"},{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D019859"},{"d":"Signal Transduction","mj":false,"ui":"D015398"}],"chemicals":[{"n":"Antioxidants","ui":"D000975","reg":"0"},{"n":"Diethylnitrosamine","ui":"D004052","reg":"3IQ78TTX1A"},{"n":"Hepatocyte Growth Factor","ui":"D017228","reg":"67256-21-7"},{"n":"Proto-Oncogene Proteins c-met","ui":"D019859","reg":"EC 2.7.10.1"},{"n":"Acetylcysteine","ui":"D000111","reg":"WYQ7N0BPYC"}],"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":"https://aacr.figshare.com/articles/journal_contribution/Supplementary_Methods_and_Materials_from_Loss_of_Hepatocyte_Growth_Factor_c-Met_Signaling_Pathway_Accelerates_Early_Stages_of_i_N_i_-nitrosodiethylamine_Induced_Hepatocarcinogenesis/22368278/1/files/39813350.pdf","s2_open_access_landing_url":"https://www.semanticscholar.org/paper/259ca2f7aa8cfbc2364b95ec545d389d353657fb","s2_open_access_license":"CCBY","s2_open_access_status":"GREEN","pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"Hepatocyte growth factor (HGF) has been reported to have both positive and negative effects on carcinogenesis. Here, we show that the loss of c-Met signaling in hepatocytes enhanced rather than suppressed the early stages of chemical hepatocarcinogenesis. c-Met conditional knockout mice (c-metfl/fl, AlbCre+/-; MetLivKO) treated with N-nitrosodiethylamine developed significantly more and bigger tumors and with a shorter latency compared with control (w/w, AlbCre+/-; Cre-Ctrl) mice. Accelerated tumor development was associated with increased rate of cell proliferation and prolonged activation of epidermal growth factor receptor (EGFR) signaling. MetLivKO livers treated with N-nitrosodiethylamine also displayed elevated lipid peroxidation, decreased ratio of reduced glutathione to oxidized glutathione, and up-regulation of superoxide dismutase 1 and heat shock protein 70, all consistent with increased oxidative stress. Likewise, gene expression profiling done at 3 and 5 months after N-nitrosodiethylamine treatment revealed up-regulation of genes associated with cell proliferation and stress responses in c-Met mutant livers. The negative effects of c-Met deficiency were reversed by chronic p.o. administration of antioxidant N-acetyl-L-cysteine. N-acetyl-L-cysteine blocked the EGFR activation and reduced the N-nitrosodiethylamine-initiated hepatocarcinogenesis to the levels of Cre-Ctrl mice. These results argue that intact HGF/c-Met signaling is essential for maintaining normal redox homeostasis in the liver and has tumor suppressor effect(s) during the early stages of N-nitrosodiethylamine-induced hepatocarcinogenesis.","claims":[{"public_id":"cl_9aba2770b0d1f66cc4a7fc730be9137a","status":"active","text":"Accelerated tumor development was associated with increased cell proliferation, prolonged epidermal growth factor receptor signaling, and markers of elevated oxidative stress.","confidence":0.95,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_9aba2770b0d1f66cc4a7fc730be9137a"},{"public_id":"cl_7006eb751f89becc46e847b26ff31df8","status":"active","text":"Chronic N-acetyl-L-cysteine administration reversed the adverse effects of c-Met deficiency, blocked epidermal growth factor receptor activation, and reduced N-nitrosodiethylamine-initiated hepatocarcinogenesis to control levels.","confidence":0.96,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_7006eb751f89becc46e847b26ff31df8"},{"public_id":"cl_eae46e2002a66171fa354cf1f9619e70","status":"active","text":"Intact HGF/c-Met signaling is required for normal liver redox homeostasis and exerts tumor-suppressor effects during the early stages of N-nitrosodiethylamine-induced hepatocarcinogenesis.","confidence":0.94,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_eae46e2002a66171fa354cf1f9619e70"},{"public_id":"cl_33b76ff6f9afe79282012fb1ae0a3790","status":"active","text":"Loss of hepatocyte c-Met signaling enhances early chemical hepatocarcinogenesis rather than suppressing it.","confidence":0.97,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_33b76ff6f9afe79282012fb1ae0a3790"},{"public_id":"cl_dcbffb4ec36323937cfaff461d85cfcc","status":"active","text":"c-Met conditional knockout mice developed more tumors, larger tumors, and shorter tumor latency after N-nitrosodiethylamine treatment than control mice.","confidence":0.98,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_dcbffb4ec36323937cfaff461d85cfcc"}],"concepts":[{"public_id":"co_48ac1a9389036bb1a0bd750010d4402c","status":"active","name":"N-nitrosodiethylamine","description":"A chemical carcinogen used to induce hepatocarcinogenesis in mice.","types":["chemical carcinogen"],"aliases":["NDEA"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_48ac1a9389036bb1a0bd750010d4402c"},{"public_id":"co_5f6f7594959a7aafb6cbc197331ecb43","status":"active","name":"cell proliferation","description":"The rate of cell division and expansion measured in the treated livers.","types":["biological process"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_5f6f7594959a7aafb6cbc197331ecb43"},{"public_id":"co_77aafc35e417615bfbccafc891b7d865","status":"active","name":"hepatocyte growth factor/c-Met signaling pathway","description":"A signaling pathway involving hepatocyte growth factor binding to the c-Met receptor in liver cells.","types":["signaling pathway"],"aliases":["HGF/c-Met signaling pathway","HGF/c-Met signaling"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_77aafc35e417615bfbccafc891b7d865"},{"public_id":"co_792f6774824d8c76ec86d4ce8fc17939","status":"active","name":"c-Met conditional knockout mice","description":"Mice engineered to lack c-Met specifically in hepatocytes.","types":["animal model"],"aliases":["MetLivKO","c-metfl/fl, AlbCre+/-; MetLivKO"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_792f6774824d8c76ec86d4ce8fc17939"},{"public_id":"co_84a10088b693ff30078f77ee5ac51338","status":"active","name":"N-nitrosodiethylamine-induced hepatocarcinogenesis","description":"Liver cancer development initiated by N-nitrosodiethylamine exposure.","types":["disease process"],"aliases":["NDEA-induced hepatocarcinogenesis"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_84a10088b693ff30078f77ee5ac51338"},{"public_id":"co_8ffd6e8ae1e8790245591461cfd6591f","status":"active","name":"oxidative stress","description":"A cellular state characterized by elevated oxidative damage and altered redox balance.","types":["biological process"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_8ffd6e8ae1e8790245591461cfd6591f"},{"public_id":"co_a7a420716a49202704505b780d9d7b37","status":"active","name":"epidermal growth factor receptor signaling","description":"A signaling pathway mediated by the epidermal growth factor receptor.","types":["signaling pathway"],"aliases":["EGFR signaling","EGFR activation"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_a7a420716a49202704505b780d9d7b37"},{"public_id":"co_b703fd6a53d27226fb0e47c2687230df","status":"active","name":"chemical hepatocarcinogenesis","description":"Liver cancer development induced by chemical carcinogens.","types":["disease process"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_b703fd6a53d27226fb0e47c2687230df"},{"public_id":"co_ce47d198e9bc0a95454c008c953a7cb4","status":"active","name":"c-Met signaling","description":"Signal transduction mediated by the c-Met receptor tyrosine kinase.","types":["signaling pathway"],"aliases":["c-Met pathway"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_ce47d198e9bc0a95454c008c953a7cb4"},{"public_id":"co_d761656d9c7bf094bbbce2700b638d4a","status":"active","name":"N-acetyl-L-cysteine","description":"An antioxidant compound administered chronically by mouth in the experiment.","types":["antioxidant"],"aliases":["NAC"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_d761656d9c7bf094bbbce2700b638d4a"},{"public_id":"co_da8e6eca614f1d7e1d0560f5ab6410ea","status":"active","name":"hepatocyte","description":"A liver parenchymal cell that is the site of c-Met signaling loss in this study.","types":["cell type"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_da8e6eca614f1d7e1d0560f5ab6410ea"},{"public_id":"co_e4bc1753c1cf91354f6c6cf7f4aaf28c","status":"active","name":"redox homeostasis","description":"The balance between reduced and oxidized states in liver tissue.","types":["physiological state"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_e4bc1753c1cf91354f6c6cf7f4aaf28c"},{"public_id":"co_f22a9bf4ec7c20ad7978937a426eea40","status":"active","name":"control mice","description":"Comparator mice with intact c-Met signaling used as the reference group.","types":["control group"],"aliases":["w/w, AlbCre+/-; 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