Genomic instability causes HGF gene activation in colon cancer cells, promoting their resistance to necroptosis.
Genomic instability causes HGF gene activation in colon cancer cells, promoting their resistance to necroptosis.
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DOI：
10.1053/j.gastro.2014.09.019
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发表时间：
2015-01
期刊：
影响因子：
29.4
通讯作者：
Zarnegar R
中科院分区：
文献类型：
--
作者：
Seneviratne D;Ma J;Tan X;Kwon YK;Muhammad E;Melhem M;DeFrances MC;Zarnegar R
Genomic instability promotes colon carcinogenesis by inducing genetic mutations, but not all genes affected by this process have been identified. We investigated whether genomic instability in human colorectal cancer (CRC) cells produces mutations in the hepatocyte growth factor (HGF) gene. We genotyped human colon tumor tissues and adjacent non-tumor tissues collected from 78 patients University of Pittsburgh Health Sciences and Veterans hospital, along with 40 human CRC and adjacent non-tumor tissues in a commercial microarray. We used cellular, biochemical, and molecular biological techniques to investigate the factors that alter HGF signaling in colon cancer cells and its effects on cell proliferation and survival. All tested human CRC tissues and cell lines that had microsatellite instability (MSI) contained truncations in the regulatory deoxyadenosine tract element (DATE) of the HGF gene promoter. The DATE was unstable in 14% (11/78) of CRC samples; DATE truncation was also polymorphic, and detected in 18% (13/78) of CRC tissues without MSI. In CRC cell lines, truncation of DATE activated expression of HGF, resulting in its autocrine signaling via MET. This promoted cell proliferation and resistance to necroptosis. HGF signaling via MET reduced levels of the receptor-interacting serine-threonine kinase 1 (RIPK1), a mediator of necroptosis, in CRC cells. High levels of HGF protein in tumor tissues correlated with lower levels of RIPK1 and shorter survival times of patients. Thirty-one percent of CRC samples contain alterations in the DATE of the HGF promoter. Disruption of the DATE increased HGF signaling via MET and reduced levels of RIPK1 and CRC cell necroptosis. DATE alteration might be used as a prognostic factor or to select patients for therapies that target HGF-MET signaling.
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影响因子：
15.9
作者：
Ma, Jihong;DeFrances, Marie C.;Zarnegar, Reza
通讯作者：
Zarnegar, Reza
影响因子：
4.1
作者：
LIU, YH;LIN, L;ZARNEGAR, R
通讯作者：
ZARNEGAR, R
影响因子：
13.5
作者：
Ma, Jihong;Zou, Chunbin;Guo, Lida;Seneviratne, Danushka S.;Tan, Xinping;Kwon, Yong-Kook;An, Jiyan;Bowser, Robert;DeFrances, Marie C.;Zarnegar, Reza
通讯作者：
Zarnegar, Reza
影响因子：
14.8
作者：
Degterev, Alexei;Hitomi, Junichi;Yuan, Junying
通讯作者：
Yuan, Junying
DOI：
10.1016/j.bbamcr.2012.10.010
发表时间：
2013-01
影响因子：
5.1
作者：
Mohapatra, Bhopal;Ahmad, Gulzar;Nadeau, Scott;Zutshi, Neha;An, Wei;Scheffe, Sarah;Dong, Lin;Feng, Dan;Goetz, Benjamin;Arya, Priyanka;Bailey, Tameka A.;Palermo, Nicholas;Borgstahl, Gloria E. O.;Natarajan, Amarnath;Raja, Srikumar M.;Naramura, Mayumi;Band, Vimla;Band, Hamid
通讯作者：
Band, Hamid