Progression of Human Renal Cell Carcinoma via Inhibition of RhoA-ROCK Axis by PARG1.
Progression of Human Renal Cell Carcinoma via Inhibition of RhoA-ROCK Axis by PARG1.
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DOI：
10.1016/j.tranon.2016.12.004
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发表时间：
2017-04
影响因子：
5
通讯作者：
Kawakami Y
中科院分区：
文献类型：
--
作者：
Miyazaki J;Ito K;Fujita T;Matsuzaki Y;Asano T;Hayakawa M;Asano T;Kawakami Y
肾细胞癌（RCC）是最致命的泌尿系统恶性肿瘤，复发风险很高；因此，需要新的预后生物标志物。在本研究中，通过使用 RCC 患者血清的重组 cDNA 表达克隆的血清学鉴定，鉴定出一种新的 RCC 抗原，PTPL1 相关 RhoGAP1 (PARG1)。研究发现 PARG1 蛋白在患者的 RCC 细胞中存在差异表达。 PARG1 高表达与癌细胞增殖和侵袭相关的各种临床病理因素显着相关，包括 G3 百分比 (P = .0046)、Ki-67 评分（p 表达还与 N0M0 患者的高复发率 (P = .0084) 和 RCC 患者的不良预后相关 (P = .0345)。多变量分析显示，PARG1 高表达是 N0M0 患者复发的独立因素 (P = .0149)在体外研究中，人 RCC 细胞系中 siRNA 的 PARG1 缺失通过 p53 的上调和随后的 p21Cip1/Waf1 诱导 G1 细胞周期停滞来抑制其增殖，这是由 RhoA-ROCK 活性增加介导的，同样，PARG1 缺失细胞通过 RhoA-ROCK 活性增加来抑制侵袭能力，相反，PARG1 的过度表达。这些结果表明，PARG1通过抑制RhoA-ROCK轴来增加细胞增殖和侵袭能力，在人肾细胞癌的进展中发挥着至关重要的作用，并且PARG1是一个不良的预后标志物，特别是对于高复发率的N0M0肾细胞癌患者。
Renal cell carcinoma (RCC) is the most lethal urological malignancy with high risk of recurrence; thus, new prognostic biomarkers are needed. In this study, a new RCC antigen, PTPL1 associated RhoGAP1 (PARG1), was identified by using serological identification of recombinant cDNA expression cloning with sera from RCC patients. PARG1 protein was found to be differentially expressed in RCC cells among patients. High PARG1 expression is significantly correlated with various clinicopathological factors relating to cancer cell proliferation and invasion, including G3 percentage (P = .0046), Ki-67 score (p expression is also correlated with high recurrence of N0M0 patients (P = .0084) and poor prognosis in RCC patients (P = .0345). Multivariate analysis has revealed that high PARG1 expression is an independent factor for recurrence (P = .0149) of N0M0 RCC patients. In in vitro studies, depletion of PARG1by siRNA in human RCC cell lines inhibited their proliferation through inducing G1 cell cycle arrest via upregulation of p53 and subsequent p21Cip1/Waf1, which are mediated by increased RhoA-ROCK activities. Similarly, PARG1 depletion cells inhibited invasion ability via increasing RhoA-ROCK activities in the RCC cell lines. Conversely, overexpression of PARG1 on human embryonic kidney cell line HEK293T promotes its cell proliferation and invasion. These results indicate that PARG1 plays crucial roles in progression of human RCC in increasing cell proliferation and invasion ability via inhibition of the RhoA-ROCK axis, and PARG1 is a poor prognostic marker, particularly for high recurrence of N0M0 RCC patients.