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α4 is highly expressed in carcinogen-transformed human cells and primary human cancers

Oncogene volume 30, pages 2943–2953 (2011)Cite this article

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Abstract

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 B1, 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.

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Acknowledgements

We thank Dr Richard Possemato for critical reading of the manuscript. This work was supported by a Distinguished Young Scholar of NSFC (30925029), Key Program of NSFC (30630055) and NSFC (30800930, 30771832, 30901211), National Key Basic Research and Development Program (2010CB912803), National High Technology Research and Development Key Program of China (2008AA062504), Ministry of Health of China (200902006), the Fundamental Research Funds for the Central Universities (10ykjc05 and 10lgzd10) and Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme GDUPS (2010).

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  1. L-P Chen, Y-D Lai and D-C Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Faculty of Preventive Medicine, School of Public Health, Sun Yat-Sen University, Guangzhou, China

    L-P Chen, Y-D Lai, D-C Li, X-N Zhu, P Yang, W-X Li, Y-M Xiao, X-M Xing, Q Wang, B Zhang, Y-C Lin, J-L Zeng, S-X Zhang, C-X Liu, Z-F Li, X-W Zeng, Z-N Lin, Z-X Zhuang & W Chen

  2. Institute for Chemical Carcinogenesis, Guangzhou Medical College, Guangzhou, China

    Y-D Lai

  3. Unit of Toxicology, Guangzhou Center for Disease Control, Guangzhou, China

    W-X Li & W Zhu

  4. Department of Thoracic Surgery, The Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, China

    J Zhao

  5. Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China

    X-D Li

  6. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China

    Y Zhang

  7. Department of Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China

    Z-X Zhuang

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Chen, LP., Lai, YD., Li, DC. et al. α4 is highly expressed in carcinogen-transformed human cells and primary human cancers. Oncogene 30, 2943–2953 (2011). https://doi.org/10.1038/onc.2011.20

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