BACKGROUND N-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. METHODS Immunohistochemistry (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. RESULTS NDRG1 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. CONCLUSION Our 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.

中文翻译：

---

N-myc下游调控的基因1通过拮抗NEDD4介导的p21泛素化来抑制结直肠癌的增殖。

背景技术N-myc下游调节基因1（NDRG1）已显示在肿瘤转移中起关键作用。最近的研究表明，NDRG1可以抑制肿瘤的生长并与肿瘤的增殖有关。但是，这些作用的潜在机制仍然不清楚。方法采用免疫组织化学方法（IHC）检测结直肠癌组织中NDRG1和p21蛋白的表达，并分析其临床意义。使用CCK-8分析，集落形成分析，流式细胞术和异种移植模型来评估NDRG1在体内和体外对肿瘤增殖的影响。使用蛋白质印迹，免疫荧光，免疫沉淀和泛素化试验研究了NDRG1作用的潜在机制。结果NDRG1在CRC组织中下调，并与肿瘤大小和患者生存率相关。NDRG1通过抑制p21泛素化增加p21的表达来抑制肿瘤的增殖。NDRG1和p21在体内和体外均呈正相关。从机制上讲，E3连接酶NEDD4可以直接与p21相互作用并靶向降解。而且，NDRG1可以拮抗NEDD4介导的p21泛素化，增加p21的表达并抑制肿瘤的扩散。结论我们的研究可以实现NDRG1在肿瘤发生和转移过程中的潜在机制，这可能是人类大肠癌的抑癌药和新疗法的潜在靶标。NDRG1和p21在体内和体外均呈正相关。从机制上讲，E3连接酶NEDD4可以直接与p21相互作用并靶向降解。而且，NDRG1可以拮抗NEDD4介导的p21泛素化，增加p21的表达并抑制肿瘤的扩散。结论我们的研究可以实现NDRG1在肿瘤发生和转移过程中的潜在机制，这可能是人类大肠癌的抑癌药和新疗法的潜在靶标。NDRG1和p21在体内和体外均呈正相关。从机制上讲，E3连接酶NEDD4可以直接与p21相互作用并靶向降解。而且，NDRG1可以拮抗NEDD4介导的p21泛素化，增加p21的表达并抑制肿瘤的扩散。结论我们的研究可以实现NDRG1在肿瘤发生和转移过程中的潜在机制，这可能是人类大肠癌的抑癌药和新疗法的潜在靶标。