期刊
ONCOTARGET
卷 7, 期 48, 页码 79003-79017出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.12984
关键词
ING4; Sp1; angiogenesis; colorectal cancer; prognosis
资金
- National Natural Science Foundation of China [81472663, 81502772]
- Education Department of Jiangsu Province [15KJA320006, 15KJB330007]
- Science and Technology Department of Jiangsu Province [BK20150222]
- China Postdoctoral Science Foundation [2015M571819]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
ING4, a potential tumor suppressor, is implicated in cell cycle arrest, apoptosis, cell migration and angiogenesis. Here, we investigated the clinical value of ING4 and its impact on angiogenesis in colorectal cancer (CRC). In this study, we found that ING4 expression was significantly reduced in CRC tissues versus paired normal colon tissues. Moreover, low ING4 expression was significantly associated with increased lymph node metastasis, advanced TNM stage and poor overall survival. Multivariate Cox regression analysis showed that ING4 expression was an independent favourable prognostic factor for CRC (hazard ratio = 0.45, P = 0.001). In addition, we found that ING4 strongly inhibited CRC angiogenesis by suppressing Sp1 expression and transcriptional activity through ubiquitin degradation and down-regulating the expressions of Sp1 downstream pro-angiogenic genes, MMP-2 and COX-2. Moreover, ING4 might inhibit phosphorylation activity of cyclin/CDK2 complexes to trigger Sp1 degradation by inducing p21 expression in despite of p53 status. Our findings imply that reduced ING4 expression in CRC resulted in increased angiogenesis and contributed to CRC metastasis and poor prognosis. Restoration of ING4 may be a novel strategy for the treatment of metastatic CRC.
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