Genome-wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target.
Genome-wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target.
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DOI：
10.1002/path.4006
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发表时间：
2012-06
影响因子：
7.3
通讯作者：
Swanton, Charles
中科院分区：
文献类型：
--
作者：
Gerlinger, Marco;Santos, Claudio R.;Spencer-Dene, Bradley;Martinez, Pierre;Endesfelder, David;Burrell, Rebecca A.;Vetter, Marcus;Jiang, Ming;Saunders, Rebecca E.;Kelly, Gavin;Dykema, Karl;Rioux-Leclercq, Nathalie;Stamp, Gordon;Patard, Jean Jacques;Larkin, James;Howell, Michael;Swanton, Charles
关键词：
透明细胞肾细胞癌（ccRCC）是肾癌最常见的病理亚型。在这里，我们将 ccRCC 生存调节因子的无偏全基因组 RNA 干扰筛选与对 ccRCC 中反复过度表达的基因的分析相结合，以确定该疾病的新治疗靶点。单羧酸转运蛋白 MCT4 (SLC16A3) 是最有效的生存调节因子之一，它会损害所有测试的八个 ccRCC 系中的 ccRCC 活力，并且在五个 ccRCC 表达数据集的荟萃分析中，它是第七个过度表达的基因。 MCT4 沉默会损害糖酵解产生的乳酸分泌，并诱导细胞周期停滞和细胞凋亡。沉默 MCT4 会导致细胞内酸中毒、细胞内 ATP 产生减少以及 ccRCC 细胞系中 Warburg 效应的部分逆转。在原发性 ccRCC 中观察到 MCT4 蛋白表达强度的瘤内异质性。基于原发性 ccRCC 中最高表达强度的 MCT4 蛋白表达分析与较差的无复发生存率相关，而模态强度与 Fuhrman 核分级相关。与疾病进展期间富含 MCT4 表达的亚克隆的潜在选择一致，MCT4 表达在转移性疾病部位更高。这些数据表明 MCT4 可能作为一种新的代谢靶点来逆转 Warburg 效应并限制 ccRCC 的疾病进展。版权所有 © 2012 大不列颠及爱尔兰病理学会。由约翰·威利父子有限公司出版
Clear cell renal cell carcinoma (ccRCC) is the most common pathological subtype of kidney cancer. Here, we integrated an unbiased genome-wide RNA interference screen for ccRCC survival regulators with an analysis of recurrently overexpressed genes in ccRCC to identify new therapeutic targets in this disease. One of the most potent survival regulators, the monocarboxylate transporter MCT4 (SLC16A3), impaired ccRCC viability in all eight ccRCC lines tested and was the seventh most overexpressed gene in a meta-analysis of five ccRCC expression datasets. MCT4 silencing impaired secretion of lactate generated through glycolysis and induced cell cycle arrest and apoptosis. Silencing MCT4 resulted in intracellular acidosis, and reduction in intracellular ATP production together with partial reversion of the Warburg effect in ccRCC cell lines. Intra-tumoural heterogeneity in the intensity of MCT4 protein expression was observed in primary ccRCCs. MCT4 protein expression analysis based on the highest intensity of expression in primary ccRCCs was associated with poorer relapse-free survival, whereas modal intensity correlated with Fuhrman nuclear grade. Consistent with the potential selection of subclones enriched for MCT4 expression during disease progression, MCT4 expression was greater at sites of metastatic disease. These data suggest that MCT4 may serve as a novel metabolic target to reverse the Warburg effect and limit disease progression in ccRCC. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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DOI：
10.1111/j.1748-1716.1974.tb05719.x
发表时间：
1974-01-01
期刊：
ACTA PHYSIOLOGICA SCANDINAVICA
影响因子：
--
作者：
KARLSSON, J;HULTEN, B;SJODIN, B
通讯作者：
SJODIN, B
DOI：
10.1038/nrurol.2010.47
发表时间：
2010-05
期刊：
Nature reviews. Urology
影响因子：
--
作者：
通讯作者：
--
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
6.2
作者：
Escudier, Bernard;Goupil, Marine Gross;Fizazi, Karim
通讯作者：
Fizazi, Karim
影响因子：
4.1
作者：
Dimmer, KS;Friedrich, B;Bröer, S
通讯作者：
Bröer, S