Zhang Weizhen, Liang Zhenyu, Li Jing
Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
Oncol Rep. 2016 May;35(5):2529-34. doi: 10.3892/or.2016.4634. Epub 2016 Feb 24.
Lung cancer is the leading cause for cancer-related death, however, the pathogenesis mechanism is poorly understood. Although the rhotekin (RTKN) gene has been reported to encode an effector for the Rho protein that has critical roles in regulating cell growth, the role of RTKN in lung cancer has not been investigated. In clinical lung cancer patient tumor samples, we identified that the RTKN gene expression level was significantly higher in tumor tissues compared to that of the adjacent normal tissues. To investigate the molecular mechanisms of RTKN in lung cancer, we established RTKN stable knock-down A549 and SPC-A-1 lung adenocarcinoma cell lines using lentiviral transfection of RTKN shRNA and evaluated the antitumor effects. The results showed that RTKN knock-down inhibited lung adenocarcinoma cell viability, induced S phase arrest and increased cell apoptosis. In addition, RTKN knock-down inhibited lung cancer cell invasion and adhesion. Further analysis showed that the S phase promoting factors cyclin-dependent kinase (CDK)1 and CDK2 levels were decreased in RTKN knock-down cells, and that the DNA replication initiation complex proteins Minichromosome maintenance protein complex (MCM)2 and MCM6 were decreased as well in RTKN knock-down cells. These results indicated that the RTKN protein was associated with lung cancer in clinic samples and exerted anticancer activity in lung adenocarcinoma cells through inhibiting cell cycle progression and the DNA replication machinery. These findings suggest that RTKN inhibition may be a novel therapeutic strategy for lung adenocarcinoma.
肺癌是癌症相关死亡的主要原因，然而，其发病机制尚不清楚。尽管已报道rhotekin（RTKN）基因编码一种Rho蛋白效应器，该效应器在调节细胞生长中起关键作用，但RTKN在肺癌中的作用尚未得到研究。在临床肺癌患者的肿瘤样本中，我们发现与相邻正常组织相比，肿瘤组织中RTKN基因表达水平显著更高。为了研究RTKN在肺癌中的分子机制，我们使用RTKN shRNA的慢病毒转染建立了RTKN稳定敲低的A549和SPC-A-1肺腺癌细胞系，并评估了其抗肿瘤作用。结果表明，RTKN敲低抑制了肺腺癌细胞的活力，诱导了S期阻滞并增加了细胞凋亡。此外，RTKN敲低抑制了肺癌细胞的侵袭和黏附。进一步分析表明，在RTKN敲低的细胞中，促进S期的因子细胞周期蛋白依赖性激酶（CDK）1和CDK2水平降低，并且DNA复制起始复合物蛋白微小染色体维持蛋白复合物（MCM）2和MCM6在RTKN敲低的细胞中也降低。这些结果表明，RTKN蛋白在临床样本中与肺癌相关，并通过抑制细胞周期进程和DNA复制机制在肺腺癌细胞中发挥抗癌活性。这些发现表明，抑制RTKN可能是肺腺癌的一种新的治疗策略。
