Sun Meng-Yao, Zhang Hong, Tao Jie, Ni Zhen-Hua, Wu Qiu-Xue, Tang Qing-Feng
Department of Clinical Laboratory and Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China,
Center for Innovative Chinese Medicine Research, Institute of Interdisciplinary Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Cancer Manag Res. 2019 Jan 25;11:1069-1080. doi: 10.2147/CMAR.S185345. eCollection 2019.
BACKGROUND/AIM: Gastric cancer (GC) is one of a most threatening cancer globally. Rhotekin (RTKN), a Rho effector, has been reported to be upregulated in GC tissues. This study aimed to investigate the underlying regulatory roles of RTKN in the biological behavior of GC.
Real-time PCR and Western blotting were carried out to detect the mRNA and protein expression, respectively. Cell Counting Kit-8 and xenograft nude mice model were used to evaluate cell proliferation. Flow cytometry analysis was performed to assess cell cycle distribution and cell apoptosis.
RTKN had high expression level in GC compared with normal tissues. RTKN expression strongly associated with tumor size, TNM stage, lymphnode metastasis and the poor prognosis of patients with GC. Downregulation of RTKN significantly repressed GC cell proliferation, but increased cell population in G1/S phase and induced cell apoptosis. Moreover, the RTKN expression level was related to the p53 signaling pathway and histone deacetylase (HDAC) Class I pathway. RTKN knockdown caused a notable increment in the acetylation level of p53 (Lys382), and the expression of p53-target genes (p21, Bax, and PUMA), as well as a reduction in the expression of a potential deacetylase for p53, HDAC1. Notably, downregulation of HDAC1 had similar effects as RTKN knockdown, and RTKN overexpression could hardly abrogate the effects of HDAC1 knockdown on GC cells.
RTKN could work as an oncogene via regulating HDAC1/p53 and may become a promising treatment strategy for GC.
背景/目的：胃癌（GC）是全球最具威胁性的癌症之一。据报道，Rhotekin（RTKN）作为一种Rho效应蛋白，在GC组织中表达上调。本研究旨在探讨RTKN在GC生物学行为中的潜在调控作用。
分别采用实时PCR和蛋白质印迹法检测mRNA和蛋白质表达。使用细胞计数试剂盒-8和异种移植裸鼠模型评估细胞增殖。进行流式细胞术分析以评估细胞周期分布和细胞凋亡。
与正常组织相比，RTKN在GC中表达水平较高。RTKN表达与肿瘤大小、TNM分期、淋巴结转移及GC患者预后不良密切相关。下调RTKN可显著抑制GC细胞增殖，但增加G1/S期细胞比例并诱导细胞凋亡。此外，RTKN表达水平与p53信号通路和I类组蛋白去乙酰化酶（HDAC）通路有关。敲低RTKN导致p53（Lys382）乙酰化水平显著升高，p53靶基因（p21、Bax和PUMA）表达增加，以及p53潜在去乙酰化酶HDAC1表达降低。值得注意的是，下调HDAC1具有与敲低RTKN相似的作用，且过表达RTKN几乎不能消除HDAC1敲低对GC细胞的影响。
RTKN可通过调节HDAC1/p53发挥癌基因作用，可能成为GC一种有前景的治疗策略。
