PDZK1 inhibits the development and progression of renal cell carcinoma by suppression of SHP-1 phosphorylation
PDZK1 inhibits the development and progression of renal cell carcinoma by suppression of SHP-1 phosphorylation
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DOI：
10.1038/onc.2017.199
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发表时间：
2017-07
期刊：
影响因子：
8
通讯作者：
T. Tao;X. Yang;Junfang Zheng;D. Feng;Q. Qin;X. Shi;Q. Wang;C. Zhao;Zhiqiang Peng;H. Liu;W. Jiang;Junqi He
中科院分区：
文献类型：
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作者：
T. Tao;X. Yang;Junfang Zheng;D. Feng;Q. Qin;X. Shi;Q. Wang;C. Zhao;Zhiqiang Peng;H. Liu;W. Jiang;Junqi He
肾细胞癌（Renal cell carcinoma，RCC）是泌尿系统最具侵袭性的恶性肿瘤之一，其发生机制尚不清楚。通过基因表达谱分析和功能聚类，PDZ domain-containing 1（PDZK 1）在人肾透明细胞癌（ccRCC）样本中表达下调，这也在几个独立的公共ccRCC数据集中得到了验证。在ccRCC细胞系中使用PDZK 1过表达和敲低模型，我们证明PDZK 1抑制细胞增殖、细胞周期G1/S期转换、细胞迁移和侵袭，表明在ccRCC的发展和进展中具有肿瘤抑制作用。我们的研究进一步证明PDZK 1通过靶向SHP-1抑制ccRCC细胞增殖和迁移。PDZK 1通过抑制SHP-1和PLCβ3之间的结合来阻断SHP-1在Tyr 536处的磷酸化，然后在ccRCC细胞中延迟Akt磷酸化并促进STAT 5磷酸化，从而进一步鉴定出PDZK 1抑制细胞增殖。此外，PDZK 1对SHP-1磷酸化和肿瘤生长的抑制作用通过异种移植肿瘤研究在体内得到验证。因此，PDZK 1表达与SHP-1活化和磷酸化、晚期病理分期、肿瘤重量和大小以及ccRCC患者的预后呈负相关。这些发现提供了第一批证据，即PDZK 1表达与SHP-1活化和ccRCC中不良临床结局呈负相关。PDZK 1通过否定SHP-1活性而被鉴定为ccRCC中的新型肿瘤抑制因子。
Renal cell carcinoma (RCC) is one of the most aggressive urologic cancers, however, the mechanism on supporting RCC carcinogenesis is still not clear. By using gene expression profile analysis and functional clustering, PDZ domain-containing 1 (PDZK1) was revealed to be downregulated in human clear cell renal cell carcinoma (ccRCC) samples, which was also verified in several independent public ccRCC data sets. Using PDZK1 overexpression and knockdown models in ccRCC cell lines, we demonstrated that PDZK1 inhibited cell proliferation, cell cycle G1/S phase transition, cell migration and invasion, indicating a tumor-suppressor role in the development and progression of ccRCC. Our study further demonstrated that PDZK1 inhibited cell proliferation and migration of ccRCC via targeting SHP-1. PDZK1 was further identified to suppress cell proliferation by blocking SHP-1 phosphorylation at Tyr536 via inhibition of the association between SHP-1 and PLCβ3, and then retarding Akt phosphorylation and promoting STAT5 phosphorylation in ccRCC cells. Moreover, the inhibitive effects of PDZK1 on SHP-1 phosphorylation and the tumor growth were verified in vivo by xenograft tumor studies. Accordingly, PDZK1 expression was negatively correlated with SHP-1 activation and phosphorylation, advanced pathologic stage, tumor weight and size, and prognosis of ccRCC patients. These findings have provided first lines of evidences that PDZK1 expression is negatively correlated with SHP-1 activation and poor clinical outcomes in ccRCC. PDZK1 was identified as a novel tumor suppressor in ccRCC by negating SHP-1 activity.