α4 is highly expressed in carcinogen-transformed human cells and primary human cancers
α4 is highly expressed in carcinogen-transformed human cells and primary human cancers
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DOI：
10.1038/onc.2011.20
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发表时间：
2011-06-01
期刊：
影响因子：
8
通讯作者：
Chen, W.
中科院分区：
文献类型：
--
作者：
Chen, L-P;Lai, Y-D;Chen, W.
蛋白磷酸酶2A（PP 2A）的调节剂α 4涉及调节许多细胞过程的多种功能。为了探索α 4在人类细胞转化和肿瘤发生中的作用，我们发现α 4在由化学致癌物包括苯并（a）芘、黄曲霉毒素B-1、N-甲基-N '-硝基-N-亚硝基胍、硫酸镍转化的人类细胞中以及在几种肝癌和肺癌细胞系中高度表达。此外，在87.5%（74/80）的原发性肝细胞癌、84.0%（21/25）的原发性肺癌和81.8%（9/11）的原发性乳腺癌中检测到α 4的过表达，表明α 4在人类癌症中普遍高表达。功能研究表明，α 4表达升高导致细胞增殖增加，促进细胞存活和PP 2A可归因活性降低。重要的是，α 4的异位表达允许非转化的人胚肾细胞（HEKTER）和L02 R细胞在免疫缺陷小鼠中形成肿瘤。此外，我们表明，在转化细胞或人类肿瘤中高度表达的α 4不受DNA低甲基化的调节。通过特异性结合α 4的3 '-非翻译区抑制α 4表达的微小RNA miR-34 b在转化的或人肺肿瘤中下调。总之，这些观察结果表明α 4具有致癌功能。由于α 4-PP 2A相互作用增强而导致的PP 2A活性降低直接有助于化学致癌物诱导的肿瘤发生。Oncogene（2011）30，2943-2953; doi：10.1038/onc.2011.20; 2011年2月21日在线发表
A regulator of the protein phosphatase 2A (PP2A), alpha 4, has been implicated in a variety of functions that regulate many cellular processes. To explore the role of alpha 4 in human cell transformation and tumorigenesis, we show that alpha 4 is highly expressed in human cells transformed by chemical carcinogens including benzo(a) pyrene, aflatoxin B-1, N-methyl-N'-nitro- N-nitrosoguanidine, nickel sulfate and in several hepatic and lung cancer cell lines. In addition, overexpression of a4 was detected in 87.5% (74/80) of primary hepatocellular carcinomas, 84.0% (21/25) of primary lung cancers and 81.8% (9/11) of primary breast cancers, indicating that a4 is ubiquitously highly expressed in human cancer. Functional studies revealed that elevated alpha 4 expression results in an increase in cell proliferation, promotion of cell survival and decreased PP2A-attributable activity. Importantly, ectopic expression of alpha 4 permits non-transformed human embryonic kidney cells (HEKTER) and L02R cells to form tumors in immunodeficient mice. Furthermore, we show that the highly expressed alpha 4 in transformed cells or human tumors is not regulated by DNA hypomethylation. A microRNA, miR-34b, that suppresses the expression of alpha 4 through specific binding to the 3'-untranslated region of alpha 4 is downregulated in transformed or human lung tumors. Taken together, these observations identify that alpha 4 possesses an oncogenic function. Reduction of PP2A activity due to an enhanced alpha 4-PP2A interaction contributes directly to chemical carcinogen-induced tumorigenesis. Oncogene (2011) 30, 2943-2953; doi:10.1038/onc.2011.20; published online 21 February 2011