Sun Kang, He Song-Bing, Yao Yi-Zhou, Qu Jian-Guo, Xie Rong, Ma Yu-Qiao, Zong Ming-Hui, Chen Ji-Xiang
1Department of General Surgery, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001 People's Republic of China.
2Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006 People's Republic of China.
Cancer Cell Int. 2019 Apr 16;19:102. doi: 10.1186/s12935-019-0823-0. eCollection 2019.
Most colorectal cancer (CRC) patients are diagnosed at an advanced or metastatic stage with poor prognosis. Ubiquitin-specific protease 6 N-terminal-like protein (USP6NL) with high expression in CRC tissues regulates CRC cell proliferation via Wnt/β-catenin pathway. We hypothesized that USP6NL impacts CRC growth and inhibition of USP6NL may be a novel treatment strategy to improve CRC therapy.
USP6NL level in human CRC tissues and its association with tumor growth and metastasis were examined. Its roles and potential mechanisms in regulating tumor growth were studied by genetic and pharmacological manipulation of CRC cells in vitro and in vivo.
Herein, we found that USP6NL was up-regulated in tumorous tissues of CRC patients. Our data suggested that knockdown of USP6NL in human CRC cell lines (HCT116 and LOVO cells) inhibited cell proliferation, induced G0/G1 cell cycle arrest, and prevented the tumorigenicity of HCT116 cells in nude mice, and which was associated with the prevention of Wnt/β-catenin pathway. On the contrary, USP6NL overexpression in human CRC cells (SW480) showed the opposite result. Our data suggested that the promoted cell proliferation, G1/S cell cycle progression, and the enhanced expression of β-catenin Cyclin D1 and C-myc while reduced P27 induced by the overexpression of USP6NL were significantly reversed by additional treatment of XAV939, indicating that activating Wnt/β-catenin pathway was the mechanism, by which USP6NL exerted carcinogenesis in CRC in vitro. Besides, our data suggested that knockdown of USP6NL increased the ubiquitination of β-catenin, indicating that USP6NL may serve as a deubiquitinase that regulated β-catenin accumulation in this process. Furthermore, 10058-F4 down-regulated USP6NL, inhibited CRC cell proliferation and induced cell cycle arrest. The result demonstrated a possible feedback loop between USP6NL, β-catenin and C-myc in regulating CRC cell growth.
USP6NL was an oncogene in CRC, and it may be a potential target for the treatment of CRC.
大多数结直肠癌（CRC）患者在晚期或转移阶段被诊断出来，预后较差。泛素特异性蛋白酶6 N端样蛋白（USP6NL）在CRC组织中高表达，通过Wnt/β-连环蛋白途径调节CRC细胞增殖。我们假设USP6NL影响CRC生长，抑制USP6NL可能是改善CRC治疗的一种新的治疗策略。
检测人CRC组织中USP6NL水平及其与肿瘤生长和转移的关系。通过体外和体内对CRC细胞进行基因和药物操作，研究其在调节肿瘤生长中的作用和潜在机制。
在此，我们发现USP6NL在CRC患者的肿瘤组织中上调。我们的数据表明，敲低人CRC细胞系（HCT116和LOVO细胞）中的USP6NL可抑制细胞增殖，诱导G0/G1细胞周期停滞，并阻止HCT116细胞在裸鼠中的致瘤性，这与阻止Wnt/β-连环蛋白途径有关。相反，人CRC细胞（SW480）中USP6NL的过表达显示出相反的结果。我们的数据表明，USP6NL过表达诱导的细胞增殖促进、G1/S细胞周期进程以及β-连环蛋白、细胞周期蛋白D1和C-myc表达增强而P27表达降低，通过额外使用XAV939处理可显著逆转，表明激活Wnt/β-连环蛋白途径是USP6NL在体外CRC中发挥致癌作用的机制。此外，我们的数据表明，敲低USP6NL可增加β-连环蛋白的泛素化，表明USP6NL可能作为一种去泛素酶在此过程中调节β-连环蛋白的积累。此外，10058-F4下调USP6NL，抑制CRC细胞增殖并诱导细胞周期停滞。结果表明在调节CRC细胞生长中USP6NL、β-连环蛋白和C-myc之间可能存在反馈回路。
USP6NL是CRC中的一个癌基因，它可能是CRC治疗的一个潜在靶点。
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