PTPN3 Inhibits the Growth and Metastasis of Clear Cell Renal Cell Carcinoma via Inhibition of PI3K/AKT Signaling
PTPN3 Inhibits the Growth and Metastasis of Clear Cell Renal Cell Carcinoma via Inhibition of PI3K/AKT Signaling
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PTPN3 通过抑制 PI3K/AKT 信号传导抑制透明细胞肾细胞癌的生长和转移
DOI：
10.1158/1541-7786.mcr-19-1142
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发表时间：
2020-06-01
影响因子：
5.2
通讯作者：
Qian, Chao-Nan
中科院分区：
文献类型：
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作者：
Peng, Xing-Si;Yang, Jun-Ping;Qian, Chao-Nan
驱动肾透明细胞癌（ccRCC）进展的潜在分子机制仍有待探索。蛋白酪氨酸磷酸酶非受体3（PTPN 3）在肿瘤组织中的表达显着下调，表明其在ccRCC进展中的保护作用。172例ccRCC组织中PTPN 3蛋白的IHC分析显示，PTPN 3是患者无进展生存期（P = 0.0166）和总生存期（P = 0.0343）的独立有利预后因素。ccRCC细胞系SN 12 C、1932、ACHN和Caki-1用于在体外和体内评估PTPN 3的生物学作用。我们观察到PTPN 3的过表达显著抑制ccRCC细胞的增殖、迁移和侵袭。相比之下，PTPN 3的敲低引起相反的效果。过表达PTPN 3抑制异种移植肿瘤生长和肺转移，体内小鼠模型显示。PTPN 3通过抑制AKT的磷酸化，从而使肾细胞癌细胞的PI 3 K/AKT信号通路失活，从而抑制肿瘤细胞的运动。此外，磷酸-AKTThr 308和磷酸-AKTSer 473的抑制逆转了肿瘤细胞迁移中PTPN 3诱导的沉默。我们的工作揭示了PTPN 3的过表达可以通过负调节AKT信号通路来抑制肾癌的进展，并在ccRCC患者中充当有利的预后因素。我们的研究结果提供了见解，PTPN 3可能是旨在抑制ccRCC恶性行为的治疗的潜在靶点。含义：PTPN 3是一个独立的有利预后因子，对ccRCC患者，并可能成为一个潜在的治疗目标，旨在抑制ccRCC的恶性行为。
The underlying molecular mechanism driving clear cell renal cell carcinoma (ccRCC) progression is still to be explored. The significant downregulation of protein tyrosine phosphatase nonreceptor type 3 (PTPN3) expression in the tumor tissues suggested its protective role in ccRCC progression. IHC analysis of PTPN3 protein in 172 ccRCC tissue revealed that PTPN3 was an independently favorable prognostic factor for progression-free survival (P = 0.0166) and overall survival (P = 0.0343) of patients. The ccRCC cell lines SN12C, 1932, ACHN, and Caki-1 were used to evaluate, both in vitro and in vivo, the biological roles of PTPN3. We observed that overexpression of PTPN3 significantly inhibited the proliferation, migration, and invasion of ccRCC cells. In contrast, the knocking down of PTPN3 elicited opposite effects. Overexpressing PTPN3 inhibited xenograft tumor growth and lung metastasis displayed by the in vivo mice models. PTPN3 inhibited tumor cell motility by suppressing the phosphorylation of AKT, and subsequently inactivating the PI3K/AKT signaling pathway of renal cell carcinoma cells. Furthermore, the inhibition of phospho-AKTThr308 and phospho-AKTSer473 reversed PTPN3-induced silencing in tumor cell migration. Our work revealed that the overexpression of PTPN3 could suppress kidney cancer progression by negatively regulating the AKT signaling pathway, and served as a favorable prognostic factor in patients with ccRCC. Our findings provided insight that PTPN3 could be a potential target for therapy aiming to inhibit the malignant behaviors of ccRCC. Implications: PTPN3 is an independent favorable prognostic factor for patients with ccRCC and could be a potential target for therapy aiming to inhibit the malignant behaviors of ccRCC.