ING4 suppresses tumor angiogenesis and functions as a prognostic marker in human colorectal cancer.
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.
Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.|School of Public Health, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.
Yansu
Y
Chen
Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.|School of Public Health, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.
Yefei
Y
Huang
Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.|Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.
Pingfu
P
Hou
Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.
Zhe
Z
Zhang
Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.
Yafei
Y
Zhang
Department of Oncology, Yixing People's Hospital, Yixing 214200, Jiangsu Province, China.
Weimin
W
Wang
School of Public Health, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.
Guixiang
G
Sun
School of Public Health, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.
Lichun
L
Xu
Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
Jianwei
J
Zhou
Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.|Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.
Jin
J
Bai
Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.|Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.
Junnian
J
Zheng
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D009367:Neoplasm Staging; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D059748:Proteolysis; D016329:Sp1 Transcription Factor / Q000737:chemistry / Q000235:genetics; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; C483230:ING4 protein, human; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D025521:Tumor Suppressor Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
ING4; Sp1; angiogenesis; colorectal cancer; prognosis