ING4 suppresses tumor angiogenesis and functions as a prognostic marker in human colorectal cancer.
ING4 suppresses tumor angiogenesis and functions as a prognostic marker in human colorectal cancer.
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ING4 抑制肿瘤血管生成并作为人类结直肠癌的预后标志物
DOI：
10.18632/oncotarget.12984
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发表时间：
2016-11-29
期刊：
影响因子：
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通讯作者：
Zheng J
中科院分区：
文献类型：
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作者：
Chen Y;Huang Y;Hou P;Zhang Z;Zhang Y;Wang W;Sun G;Xu L;Zhou J;Bai J;Zheng J
ING4是一种潜在的肿瘤抑制因子，与细胞周期停滞、细胞凋亡、细胞迁移和血管生成有关。在这里，我们研究了ING4的临床价值及其对结直肠癌血管生成的影响。在这项研究中，我们发现ING4在结直肠癌组织中的表达显著低于配对的正常结肠组织。此外，ING4的低表达与淋巴结转移增加、TNM分期进展和总体生存不良显著相关。多因素COX回归分析显示，ING4表达是影响结直肠癌预后的独立因素(风险比=0.45，P=0.001)。此外，我们还发现ING4通过泛素降解抑制Sp1的表达和转录活性，并下调Sp1下游促血管生成基因MMP2和COX-2的表达，从而强烈抑制结直肠癌的血管生成。此外，ING4可能通过诱导p21的表达而抑制细胞周期蛋白/CDK2复合体的磷酸化活性，从而引发Sp1降解，而与P53状态无关。我们的研究结果表明，ING4在结直肠癌中的表达减少导致血管生成增加，从而导致结直肠癌转移和预后不良。ING4的恢复可能是治疗转移性结直肠癌的一种新策略。
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.