Journal Article

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

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

2011

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 3' Untranslated regions / 692/420/755 / 692/699/67 / Aflatoxin B1 / Animals / Apoptosis / Base Sequence / Benzo(a)pyrene / Biological and medical sciences / Breast cancer / Cancer / Carcinogens / Care and treatment / Cell Biology / Cell Line, Transformed / Cell physiology / Cell proliferation / Cell survival / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Cell Transformation, Neoplastic - chemically induced / Cell Transformation, Neoplastic - drug effects / Cell Transformation, Neoplastic - genetics / Cell Transformation, Neoplastic - metabolism / Ectopic expression / Fundamental and applied biological sciences. Psychology / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Gene Knockdown Techniques / Genetic aspects / Hep G2 Cells / Hepatocellular carcinoma / Human Genetics / Humans / Immunodeficiency / Internal Medicine / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Intracellular Signaling Peptides and Proteins - physiology / Kidneys / Liver cancer / Lung cancer / Medicine / Medicine & Public Health / Mice / Mice, Inbred BALB C / Mice, Nude / MicroRNAs - physiology / miRNA / Molecular and cellular biology / Neoplasms - chemically induced / Neoplasms - genetics / Nickel / Oncology / original-article / Phosphatases / Phosphoprotein phosphatase / Physiological aspects / Protein phosphatase / RNA, Small Interfering - pharmacology / Transformed cells / Transplantation, Heterologous / Tumor cell lines / Tumor Cells, Cultured / Tumorigenesis / Tumors / Up-Regulation