ING4 suppresses tumor angiogenesis and functions as a prognostic marker in human colorectal cancer
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Yansu Chen1,2,*, Yefei Huang1,2,*, Pingfu Hou1,3, Zhe Zhang1, Yafei Zhang1, Weimin Wang4, Guixiang Sun2, Lichun Xu2, Jianwei Zhou5, Jin Bai1,3, Junnian Zheng1,3
1Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
2School of Public Health, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
3Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
4Department of Oncology, Yixing People’s Hospital, Yixing 214200, Jiangsu Province, China
5Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
*These authors contributed equally to this work
Jin Bai, email: firstname.lastname@example.org
Junnian Zheng, email: email@example.com
Keywords: ING4, Sp1, angiogenesis, colorectal cancer, prognosis
Received: July 06, 2016 Accepted: October 22, 2016 Published: October 27, 2016
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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