Poly(U) binding splicing factor 60 promotes renal cell carcinoma growth by transcriptionally upregulating telomerase reverse transcriptase.
Poly(U) binding splicing factor 60 promotes renal cell carcinoma growth by transcriptionally upregulating telomerase reverse transcriptase.
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Poly(U)结合剪接因子60通过转录上调端粒酶逆转录酶促进肾细胞癌生长
DOI：
10.7150/ijbs.45115
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发表时间：
2020
影响因子：
9.2
通讯作者：
Deng W
中科院分区：
文献类型：
--
作者：
Long Q;Hua Y;He L;Zhang C;Sui S;Li Y;Qiu H;Tian T;An X;Luo G;Yan Y;Zhao A;Shi D;Xie F;Chen M;Zheng F;Deng W
背景资料：端粒酶逆转录酶（telomerase reverse transcriptase，TERT）的异常转录上调在多种癌症中的端粒酶激活中起主导作用。TERT启动子突变（TPM）已被确定为TERT上调的关键机制。然而，迄今为止，在具有低频率TPM的癌症中TERT上调的机制尚未完全阐明。方法：采用实时荧光定量PCR、免疫印迹和免疫组化方法检测PUF 60和TERT的表达。通过链霉亲和素-琼脂糖下拉分析和质谱（MS）分析鉴定TERT启动子结合蛋白。通过体外和体内细胞生长评估PUF 60/TERT在肾癌中的作用。结果如下：在这项研究中，我们确定了肾癌（RCC）细胞中的端粒酶逆转录酶的调节机制，这些细胞具有罕见的TPM，但端粒酶逆转录酶显着上调。我们发现，肾癌组织中的TERT高表达，并且TERT表达升高与患者的预后不良相关。我们还检测到相对罕见的TPM状态在RCC肿瘤组织和RCC细胞系。从机制上讲，PUF 60，一种RNA结合蛋白，被鉴定为一种新的TERT调节剂，其结合到RCC细胞中的TERT并转录上调TERT表达。体外和体内实验也表明PUF 60可以通过激活端粒酶的表达促进肾癌细胞的生长，而不依赖于TPM状态。PUF 60和TERT在肾细胞癌组织和细胞系中的表达具有很强的相关性，PUF 60和TERT高表达的患者生存期明显缩短。结论：总之，这些结果表明，PUF 60转录上调TERT表达，以TPM状态独立的方式促进RCC生长和进展，表明PUF 60/TERT信号通路可能作为RCC的潜在预后生物标志物和治疗靶点。
Background: Abnormal transcriptional upregulation of telomerase reverse transcriptase (TERT) plays a dominant role in telomerase activation in various cancers. TERT promoter mutations (TPMs) have been identified as a key mechanism in TERT upregulation. However, the mechanism of TERT upregulation in cancers with low frequency of TPMs are not fully elucidated so far. Methods: The expression of PUF60 and TERT was detected by real-time PCR, western blot and immunohistochemistry. TERT promoter binding proteins were identified by streptavidin-agarose pulldown assay and mass spectrum (MS) analysis. The role of PUF60/TERT in renal cancer was evaluated on cell growth in vitro and in vivo. Results: In this study, we identify the regulation mechanism of TERT in renal cell carcinoma (RCC) cells which have rare TPMs but exert significant upregulation of TERT. We found that TERT was highly expressed in RCC tumor tissues, and elevated TERT expression was associated with poor prognosis for patients. We also detected the relatively rare TPM status in both RCC tumor tissues and RCC cell lines. Mechanistically, PUF60, a RNA binding protein, was identified as a novel TERT regulator which bound to the TERT and transcriptionally upregulated TERT expression in RCC cells. The in vitro and in vivo experiments also demonstrated that PUF60 could promote RCC cell growth through activation of TERT expression in a TPM status independent way. Furthermore, we showed that there was a strong correlation of the expression of PUF60 and TERT in RCC tumor tissues and RCC cell lines, and the patients with high expression of PUF60 and TERT had significantly shorter survival. Conclusions: Collectively, these results indicated that PUF60 transcriptionally upregulated TERT expression to promote RCC growth and progression in a TPM status independent way, suggesting that the PUF60/TERT signaling pathway may serve as potential prognostic biomarkers and therapeutic targets for RCC.
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DOI：
10.1056/nejmoa1407279
发表时间：
2015-06-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Eckel-Passow JE;Lachance DH;Molinaro AM;Walsh KM;Decker PA;Sicotte H;Pekmezci M;Rice T;Kosel ML;Smirnov IV;Sarkar G;Caron AA;Kollmeyer TM;Praska CE;Chada AR;Halder C;Hansen HM;McCoy LS;Bracci PM;Marshall R;Zheng S;Reis GF;Pico AR;O'Neill BP;Buckner JC;Giannini C;Huse JT;Perry A;Tihan T;Berger MS;Chang SM;Prados MD;Wiemels J;Wiencke JK;Wrensch MR;Jenkins RB
通讯作者：
Jenkins RB
影响因子：
11.2
作者：
Matsushita, K;Tomonaga, T;Ochiai, T
通讯作者：
Ochiai, T
影响因子：
23.4
作者：
Allory, Yves;Beukers, Willemien;Real, Francisco X.
通讯作者：
Real, Francisco X.
DOI：
10.1126/science.1229259
发表时间：
2013-02-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Huang FW;Hodis E;Xu MJ;Kryukov GV;Chin L;Garraway LA
通讯作者：
Garraway LA
影响因子：
16
作者：
Liu, JH;He, LS;Levens, D
通讯作者：
Levens, D