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Notch 1是针对透明细胞肾细胞癌中细胞存活和增殖的一个有价值的治疗靶点。

Notch 1 is a valuable therapeutic target against cell survival and proliferation in clear cell renal cell carcinoma.

作者信息

Zhuang Zhiming, Lin Jiangui, Huang Yiqun, Lin Tianqi, Zheng Zhouda, Ma Xudong

机构信息

Department of Urology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian 363000, P.R. China.

Department of Hematology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian 363000, P.R. China.

出版信息

Oncol Lett. 2017 Sep;14(3):3437-3444. doi: 10.3892/ol.2017.6587. Epub 2017 Jul 15.

Abstract

Notch 1 is a key component of the Notch pathway, which performs a crucial role in clear cell renal cell carcinoma (CCRCC) development. The present study aimed to investigate whether Notch 1 could serve as a potential target for CCRCC treatment. Firstly, an association analysis was performed using 52 CCRCC cases and 30 normal controls. The results indicated that Notch 1 protein expression in renal tissues was closely associated with the incidence of CCRCC. In addition, higher Notch 1 expression in CCRCC tissues was positively associated with higher tumor-node-metastasis stage and Fuhrman grade, in addition to larger tumor size. Subsequently, an study was conducted to examine the biological functions of Notch 1 in CCRCC 786-O cells through inhibiting the Notch 1 expression with Notch 1-specific small interfering RNA (siRNA). As a result, the inhibition of Notch 1 expression by increasing concentrations of Notch 1-specific siRNA dose-dependently decreased cell proliferation and increased cell apoptosis in 786-O cells. Furthermore, B-cell lymphoma-2 and procaspase-3 expression exhibited a dose-dependent decrease accompanied with a dose-dependent inactivation of the Akt/mammalian target of rapamycin (mTOR) signaling pathway in Notch 1 siRNA-treated 786-O cells. These findings demonstrated that Notch 1 was associated with CCRCC carcinogenesis and progression, the underlying mechanism of which was that Notch 1 acted as an activator for cell proliferation and a suppressor for cell apoptosis through the Akt/mTOR signaling-dependent pathway in CCRCC. In conclusion, the present study confirmed that Notch 1 is a valuable target against cell survival and proliferation in CCRCC treatment.

摘要

Notch 1是Notch信号通路的关键组成部分,在透明细胞肾细胞癌(CCRCC)的发展中起着至关重要的作用。本研究旨在探讨Notch 1是否可作为CCRCC治疗的潜在靶点。首先,对52例CCRCC病例和30例正常对照进行了关联分析。结果表明,肾组织中Notch 1蛋白表达与CCRCC的发生率密切相关。此外,CCRCC组织中较高的Notch 1表达除了与更大的肿瘤大小相关外,还与更高的肿瘤-淋巴结-转移分期和Fuhrman分级呈正相关。随后,通过用Notch 1特异性小干扰RNA(siRNA)抑制Notch 1表达,对CCRCC 786-O细胞中Notch 1的生物学功能进行了研究。结果,随着Notch 1特异性siRNA浓度的增加对Notch 1表达的抑制呈剂量依赖性地降低了786-O细胞的增殖并增加了细胞凋亡。此外,在Notch 1 siRNA处理的786-O细胞中,B细胞淋巴瘤-蛋白2和原半胱天冬酶-3的表达呈剂量依赖性降低,同时伴有Akt/雷帕霉素哺乳动物靶标(mTOR)信号通路的剂量依赖性失活。这些发现表明,Notch 1与CCRCC的发生和进展相关,其潜在机制是Notch 1在CCRCC中通过Akt/mTOR信号依赖途径作为细胞增殖的激活剂和细胞凋亡的抑制剂。总之,本研究证实Notch 1是CCRCC治疗中对抗细胞存活和增殖的有价值靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cc6/5587946/f481aaaedd29/ol-14-03-3437-g00.jpg

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