N-myc downstream-regulated gene 1 inhibits the proliferation of colorectal cancer through emulative antagonizing NEDD4-mediated ubiquitylation of p21
N-myc downstream-regulated gene 1 inhibits the proliferation of colorectal cancer through emulative antagonizing NEDD4-mediated ubiquitylation of p21
复制标题
N-myc下游调控基因1通过模拟拮抗NEDD4介导的p21泛素化抑制结直肠癌增殖
DOI：
10.1186/s13046-019-1476-5
复制
发表时间：
2019
影响因子：
11.3
通讯作者：
Minhua Zheng
中科院分区：
文献类型：
--
作者：
Sen Zhang;Chaoran Yu;Xiao Yang;Hiju Hong;Jiaoyang Lu;Wenjun Hu;Xiaohui Hao;Shuchun Li;Batuer Aikemu;Guang Yang;Zirui He;Luyang Zhang;Pei Xue;Zhenghao Cai;Junjun Ma;Lu Zang;Bo Feng;Fei Yuan;Jing Sun;Minhua Zheng
背景N-myc下游调节基因1（NDRG 1）在肿瘤转移中起关键作用。近年来的研究表明NDRG 1具有抑制肿瘤生长的作用，并与肿瘤增殖有关，但其作用机制尚不清楚。方法采用免疫组化（IHC）方法检测NDRG 1和p21蛋白在大肠癌组织中的表达，并分析其临床意义。采用CCK-8法、集落形成法、流式细胞术和裸鼠移植瘤模型观察NDRG 1对肿瘤生长的影响。结果NDRG 1在结直肠癌组织中表达下调，并与肿瘤大小和患者生存率相关。NDRG 1通过抑制p21泛素化增加p21表达抑制肿瘤增殖。NDRG 1和p21在体内外均呈正相关。在机制上，E3连接酶NEDD 4可以直接与p21相互作用并靶向p21进行降解。结论NDRG 1在大肠癌发生、转移过程中的作用机制可能是一个潜在的抑癌基因，为大肠癌的治疗提供新的靶点。
BackgroundN-myc downstream-regulated gene 1 (NDRG1) has been shown to play a key role in tumor metastasis. Recent studies demonstrate that NDRG1 can suppress tumor growth and is related to tumor proliferation; however, the mechanisms underlying these effects remain obscure.MethodsImmunohistochemistry (IHC) was used to detect NDRG1 and p21 protein expression in colorectal cancer tissue, and clinical significance of NDRG1 was also analyzed. CCK-8 assay, colony formation assay, flow cytometry, and xenograft model were used to assess the effect of NDRG1 on tumor proliferation in vivo and in vitro. The mechanisms underlying the effect of NDRG1 were investigated using western blotting, immunofluorescence, immunoprecipitation, and ubiquitylation assay.ResultsNDRG1 was down-regulated in CRC tissues and correlated with tumor size and patient survival. NDRG1 inhibited tumor proliferation through increasing p21 expression via suppressing p21 ubiquitylation. NDRG1 and p21 had a positive correlation both in vivo and in vitro. Mechanistically, E3 ligase NEDD4 could directly interact with and target p21 for degradation. Moreover, NDRG1 could emulatively antagonize NEDD4-mediated ubiquitylation of p21, increasing p21 expression and inhibit tumor proliferation.ConclusionOur study could fulfill potential mechanisms of the NDRG1 during tumorigenesis and metastasis, which may serve as a tumor suppressor and potential target for new therapies in human colorectal cancer.