Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, Faculty of Preventive Medicine, School of Public Health, Sun Yat-Sen University, Guangzhou, China.
Oncogene. 2011 Jun 30;30(26):2943-53. doi: 10.1038/onc.2011.20. Epub 2011 Feb 21.
A regulator of the protein phosphatase 2A (PP2A), α4, has been implicated in a variety of functions that regulate many cellular processes. To explore the role of α4 in human cell transformation and tumorigenesis, we show that α4 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 α4 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 α4 is ubiquitously highly expressed in human cancer. Functional studies revealed that elevated α4 expression results in an increase in cell proliferation, promotion of cell survival and decreased PP2A-attributable activity. Importantly, ectopic expression of α4 permits non-transformed human embryonic kidney cells (HEKTER) and L02R cells to form tumors in immunodeficient mice. Furthermore, we show that the highly expressed α4 in transformed cells or human tumors is not regulated by DNA hypomethylation. A microRNA, miR-34b, that suppresses the expression of α4 through specific binding to the 3'-untranslated region of α4 is downregulated in transformed or human lung tumors. Taken together, these observations identify that α4 possesses an oncogenic function. Reduction of PP2A activity due to an enhanced α4-PP2A interaction contributes directly to chemical carcinogen-induced tumorigenesis.
蛋白磷酸酶 2A（PP2A）的一种调节因子 α4 参与了多种功能，这些功能调节着许多细胞过程。为了探讨 α4 在人类细胞转化和肿瘤发生中的作用，我们发现 α4 在化学致癌物（包括苯并[a]芘、黄曲霉毒素 B(1)、N-甲基-N'-硝基-N-亚硝胍、硫酸镍）转化的人类细胞以及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 α4 的过表达，表明 α4 在人类癌症中普遍高度表达。功能研究表明，α4 表达水平的升高会导致细胞增殖增加、促进细胞存活和降低与 PP2A 相关的活性。重要的是，α4 的异位表达使未转化的人胚肾细胞（HEKTER）和 L02R 细胞能够在免疫缺陷小鼠中形成肿瘤。此外，我们发现转化细胞或人类肿瘤中高度表达的 α4 不受 DNA 低甲基化的调节。一种 microRNA，miR-34b，通过与 α4 的 3'非翻译区特异性结合来抑制 α4 的表达，在转化或人类肺癌肿瘤中下调。综上所述，这些观察结果表明 α4 具有致癌功能。由于 α4-PP2A 相互作用增强导致的 PP2A 活性降低直接导致化学致癌物诱导的肿瘤发生。
