Decreasing CNPY2 Expression Diminishes Colorectal Tumor Growth and Development through Activation of p53 Pathway
Decreasing CNPY2 Expression Diminishes Colorectal Tumor Growth and Development through Activation of p53 Pathway
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DOI：
10.1016/j.ajpath.2015.11.012
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发表时间：
2016-04-01
影响因子：
6
通讯作者：
Li, Ren-Ke
中科院分区：
文献类型：
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作者：
Yan, Ping;Gong, Hui;Li, Ren-Ke
新生血管驱动肿瘤的发展，血管生成因子是重要的新生血管启动因子。我们最近发现了分泌血管生成因子CNPY2，但其在癌症中的作用尚未被探索。在此，我们研究了CNPY2在人类结直肠癌（CRC）发展中的作用。肿瘤样本取自接受手术的结直肠癌患者。分析了冠层2 （Canopy 2, CNPY2）在肿瘤及邻近正常组织中的表达。建立了表达CNPY2 shRNA或对照shRNA的人HCT116细胞系。为了确定CNPY2在体内对肿瘤异种移植物的影响，将人CNPY2 shRNA HCT116细胞和对照组分别注射到裸鼠体内。观察异种移植物的细胞凋亡、生长和血管生成情况。CNPY2在结直肠癌组织中的表达明显升高。敲低CNPY2抑制HCT116细胞生长和迁移，促进细胞凋亡。在异种移植物中，CNPY2敲低可阻止肿瘤生长和血管生成，并促进细胞凋亡。在HCT116 CRC细胞系中敲低CNPY2可可逆地增加p53活性。p53的激活增加了周期蛋白依赖性激酶抑制剂p21，降低了周期蛋白依赖性激酶2，从而在体外和体内抑制肿瘤细胞生长，诱导细胞凋亡，减少血管生成。CNPY2可能通过促进细胞增殖、迁移和血管生成以及通过负调控p53通路抑制细胞凋亡，在结直肠癌的发展中发挥关键作用。因此，CNPY2可能是一种新的结直肠癌治疗靶点和预后指标。
Neovascularization drives tumor development, and angiogenic factors are important neovascularization initiators. We recently identified the secreted angiogenic factor CNPY2, but its involvement in cancer has not been explored. Herein, we investigate CNPY2's role in human colorectal cancer (CRC) development. Tumor samples were obtained from CRC patients undergoing surgery. Canopy 2 (CNPY2) expression was analyzed in tumor and adjacent normal tissue. Stable lines of human HCT116 cells expressing CNPY2 shRNA or control shRNA were established. To determine CNPY2's effects on tumor xenografts in vivo, human CNPY2 shRNA HCT116 cells and controls were injected into nude mice, separately. Cellular apoptosis, growth, and angiogenesis in the xenografts were evaluated. CNPY2 expression was significantly higher in CRC tissues. CNPY2 knockdown in HCT116 cells inhibited growth and migration and promoted apoptosis. In xenografts, CNPY2 knockdown prevented tumor growth and angiogenesis and promoted apoptosis. Knockdown of CNPY2 in the HCT116 CRC cell line reversibly increased p53 activity. The p53 activation increased cyclin-dependent kinase inhibitor p21 and decreased cyclin-dependent kinase 2, thereby inhibiting tumor cell growth, inducing cell apoptosis, and reducing angiogenesis both in vitro and in vivo. CNPY2 may play a critical role in CRC development by enhancing cell proliferation, migration, and angiogenesis and by inhibiting apoptosis through negative regulation of the p53 pathway. Therefore, CNPY2 may represent a novel CRC therapeutic target and prognostic indicator.