title: α4 is highly expressed in carcinogen-transformed human cells and primary human cancers.
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 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.
authors.affiliation: 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.
authors.forename: L-P
authors.initials: LP
authors.lastname: Chen
authors.forename: Y-D
authors.initials: YD
authors.lastname: Lai
authors.forename: D-C
authors.initials: DC
authors.lastname: Li
authors.forename: X-N
authors.initials: XN
authors.lastname: Zhu
authors.forename: P
authors.initials: P
authors.lastname: Yang
authors.forename: W-X
authors.initials: WX
authors.lastname: Li
authors.forename: W
authors.initials: W
authors.lastname: Zhu
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.forename: X-D
authors.initials: XD
authors.lastname: Li
authors.forename: Y-M
authors.initials: YM
authors.lastname: Xiao
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: X-M
authors.initials: XM
authors.lastname: Xing
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.forename: Y-C
authors.initials: YC
authors.lastname: Lin
authors.forename: J-L
authors.initials: JL
authors.lastname: Zeng
authors.forename: S-X
authors.initials: SX
authors.lastname: Zhang
authors.forename: C-X
authors.initials: CX
authors.lastname: Liu
authors.forename: Z-F
authors.initials: ZF
authors.lastname: Li
authors.forename: X-W
authors.initials: XW
authors.lastname: Zeng
authors.forename: Z-N
authors.initials: ZN
authors.lastname: Lin
authors.forename: Z-X
authors.initials: ZX
authors.lastname: Zhuang
authors.forename: W
authors.initials: W
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D002273:Carcinogens; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000502:physiology; D018832:Molecular Chaperones; D009369:Neoplasms / Q000139:chemically induced / Q000235:genetics*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002273:Carcinogens; C490467:IGBP1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D018832:Molecular Chaperones; D034741:RNA, Small Interfering