中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R

留言板

尊敬的读者、作者、审稿人, 关于本刊的投稿、审稿、编辑和出版的任何问题, 您可以本页添加留言。我们将尽快给您答复。谢谢您的支持!

姓名
邮箱
手机号码
标题
留言内容
验证码

蛋白磷酸酶2A在肝细胞癌中的促进与抑制作用机制

杨成雷 黄燊 张志明

引用本文:
Citation:

蛋白磷酸酶2A在肝细胞癌中的促进与抑制作用机制

DOI: 10.3969/j.issn.1001-5256.2019.05.044
基金项目: 

广西教育厅中青年教师基础能力提升项目(KY2016YB085); 

详细信息
  • 中图分类号: R735.7

Mechanism of action of protein phosphatase 2A in the promotion and inhibition of hepatocellular carcinoma

Research funding: 

 

  • 摘要: 蛋白磷酸酶2A(PP2A)是一种主要的丝氨酸/苏氨酸磷酸酶,参与细胞生长和增殖相关的许多信号传导途径,并调节许多细胞过程。随着对PP2A在细胞活动(尤其恶性肿瘤)过程中的深入探索,其与肝细胞癌(HCC)的关系也引起了越来越多的关注和研究。PP2A对HCC的调节作用是促进还是抑制,目前仍然存在较大争议。探讨了现阶段PP2A作为肿瘤因子调控HCC的作用机制和靶点治疗的研究进展。

     

  • [1] CHEN W, ZHENG R, BAADE PD, et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66:115-132.
    [2] LIM KC, CHOW PK, ALLEN JC, et al. Systematic review of outcomes of liver resection for early hepatocellular carcinoma within the Milan criteria[J]. Br J Surg, 2012, 99 (12) :1622-1629.
    [3] ZHONG JH, KE Y, WANG YY, et al. Liver resection for patients with hepatocellular carcinoma and macrovascular invasion, multiple tumours, or portal hypertension[J]. Gut, 2015, 64 (3) :520-521.
    [4] ZHONG JH, KE Y, GONG WF, et al. Hepatic resection associated with good survival for selected patients with intermediate and advanced-stage hepatocellular carcinoma[J]. Ann Surg, 2014, 260 (2) :329-340.
    [5] EICHHOERN PJ, CREYGHTON MP, BERNARDS R. Protein phosphatase 2A regulatory subunits and cancer[J]. Biochim Biophys Acta, 2009, 1795 (1) :1-15.
    [6] KAUKO O, IMANISHI SY, KULESSKIY E, et al. Rules for PP2Acontrolled phosphosignalling and drug responses[J]. BioRxiv, 2018.[Epub ahead of print]
    [7] SHI Y. Serine/threonine phosphatases:Mechanism through structure[J]. Cell, 2009, 139:468-484.
    [8] SHOUSE G, de NECOCHEA-CAMPION R, MIRSHAHIDI S, et al. Novel B55alpha-PP2A mutations in AML promote AKT T308 phosphorylation and sensitivity to AKT inhibitor-induced growth arrest[J]. Oncotarget, 2016, 7 (38) :61081-61092.
    [9] O'CONNOR CM, PERL A, LEONAID D, et al. Therapeutic targeting of PP2A[J]. Int J Biochem Cell Biol, 2018, 96:182-193.
    [10] KAUKO O, WESTERMARCK J. Non-genomic mechanisms of protein phosphatase 2A (PP2A) regulation in cancer[J]. Int J Biochem Cell Biol, 2018, 96:157-164.
    [11] NEVIANI P, HARB JG, OAKS JJ, et al. PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells[J]. J Clin Invest, 2013, 123 (10) :4144-4157.
    [12] LAINE A, SIHTO H, COME C, et al. Senescence sensitivity of breast cancer cells is defined by positive feedback loop between CIP2A and E2F1[J]. Cancer Discov, 2013, 3 (2) :182-197.
    [13] FUKUAWA C, SHIMA H, TANUMA N, et al. Up-regulation of I-2 (PP2A) /SET gene expression in rat primary hepatomas and regenerating livers[J]. Cancer Lett, 2000, 161 (1) :89-95.
    [14] HUNG MH, CHEN YL, CHU PY, et al. Upregulation of the oncoprotein SET determines poor clinical outcomes in hepatocellular carcinoma and shows therapeutic potential[J]. Oncogene, 2016, 35 (37) :4891-4902.
    [15] ZHAI B, HU F, JIANG X, et al. Inhibition of Akt reverses the acquired resistance to sorafenib by switching protective autophagy to autophagic cell death in hepatocellular carcinoma[J]. Mol Cancer Ther, 2014, 13 (6) :1589-1598.
    [16] TORTI D, TRUSOLINO L. Oncogene addiction as a foundational rationale for targeted anti-cancer therapy:Promises and perils[J]. EMBO Mol Med, 2011, 3 (11) :623-636.
    [17] HUANG CY, HUNG MH, SHIH CT, et al. Antagonizing SET augments the effects of radiation therapy in hepatocellular carcinoma through reactivation of PP2A-mediated Akt downregulation[J]. J Pharmacol Exp Ther, 2018, 366 (3) :410-421.
    [18] JUNTTILA MR, PUUSTINEN P, NIEMELA M, et al. CIP2A inhibits PP2A in human malignancies[J]. Cell, 2007, 130 (1) :51-62.
    [19] HUANG P, QIU J, YOU J, et al. Expression and prognostic significance of CIP2A mRNA in hepatocellular carcinoma and nontumoral liver tissues[J]. Biomarkers, 2012, 17 (5) :422-429.
    [20] YU HC, HUNG MH, CHEN YL, et al. Erlotinib derivative inhibits hepatocellular carcinoma by targeting CIP2A to reactivate protein phosphatase 2A[J]. Cell Death Dis, 2014, 5:e1359.
    [21] HE H, WU G, LI W, et al. CIP2A is highly expressed in hepatocellular carcinoma and predicts poor prognosis[J]. Diagn Mol Pathol, 2012, 21 (3) :143-149.
    [22] YANG X, QU K, TAO J, et al. Inhibition of CIP2A attenuates tumor progression by inducing cell cycle arrest and promoting cellular senescence in hepatocellular carcinoma[J]. Biochem Biophys Res Commun, 2018, 495 (2) :1807-1814.
    [23] QU K, XU X, LIU C, et al. Negative regulation of transcription factor FoxM1 by p53 enhances oxaliplatin-induced senescence in hepatocellular carcinoma[J]. Cancer Lett, 2013, 331 (1) :105-114.
    [24] RITORTO MS, BORLAK J. Combined serum and tissue proteomic study applied to a c-Myc transgenic mouse model of hepatocellular carcinoma identified novel disease regulated proteins suitable for diagnosis and therapeutic intervention strategies[J]. J Proteome Res, 2011, 10 (7) :3012-3030.
    [25] RITORTO MS, HODE H, VOGELl A, et al. Regulation of glycosylphosphatidylinositol-anchored proteins and GPI-phospholipase D in a c-Myc transgenic mouse model of hepatocellular carcinoma and human HCC[J]. Biol Chem, 2016, 397 (11) :1147-1162.
    [26] LIU L, WANG D, WANG J, et al. The nitric oxide prodrug JS-K induces Ca (2+) -mediated apoptosis in human hepatocellular carcinoma HepG2 cells[J]. J Biochem Mol Toxicol, 2016, 30 (4) :192-199.
    [27] LIU L, HUANG Z, CHEN J, et al. Protein phosphatase 2A mediates JS-K-induced apoptosis by affecting Bcl-2 family proteins in human hepatocellular carcinoma HepG2 cells[J].J Cell Biochem, 2018, 119 (8) :6633-6643.
    [28] LIU L, HUANG Z, CHEN J, et al. Protein phosphatase 2A activation mechanism contributes to JS-K induced caspasedependent apoptosis in human hepatocellular carcinoma cells[J]. J Exp Clin Cancer Res, 2018, 37 (1) :142.
    [29] RIGANTI C, GAZZANO E, POLIMENI M, et al. The pentose phosphate pathway:An antioxidant defense and a crossroad in tumor cell fate[J]. Free Radic Biol Med, 2012, 53 (3) :421-436.
    [30] TONG X, ZHAO F, THOMPSON CB. The molecular determinants of de novo nucleotide biosynthesis in cancer cells[J].Curr Opin Genet Dev, 2009, 19 (1) :32-37.
    [31] CHIEN W, SUN QY, LEE KL, et al. Activation of protein phosphatase 2A tumor suppressor as potential treatment of pancreatic cancer[J]. Mol Oncol, 2015, 9 (4) :889-905.
    [32] WANG CT, CHEN YC, WANG YY, et al. Reduced neuronal expression of ribose-5-phosphate isomerase enhances tolerance to oxidative stress, extends lifespan, and attenuates polyglutamine toxicity in Drosophila[J]. Aging Cell, 2012, 11 (1) :93-103.
    [33] CIOU SC, CHOU YT, LIU YL, et al. Ribose-5-phosphate isomerase A regulates hepatocarcinogenesis via PP2A and ERK signaling[J]. Int J Cancer, 2015, 137 (1) :104-115.
    [34] KABASHIMA T, KAWAGUCHI T, WADZINSKI BE, et al. Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver[J]. Proc Natl Acad Sci U S A, 2003, 100 (9) :5107-5112.
    [35] DUNG TD, CHANG HC, BINH TV, et al. Zanthoxylum avicennae extracts inhibit cell proliferation through protein phosphatase 2A activation in HA22T human hepatocellular carcinoma cells in vitro and in vivo[J]. Int J Mol Med, 2012, 29 (6) :1045-1052.
    [36] GEDALY R, GALUPPO R, DAILY MF, et al. Targeting the Wnt/beta-catenin signaling pathway in liver cancer stem cells and hepatocellular carcinoma cell lines with FH535[J].PLo S One, 2014, 9 (6) :e99272.
    [37] GILES RH, VAN ES JH, Clevers H. Caught up in a Wnt storm:Wnt signaling in cancer[J]. Biochim Biophys Acta, 2003, 1653 (1) :1-24.
    [38] THOMPSON MD, MONGA SP. WNT/beta-catenin signaling in liver health and disease[J]. Hepatology, 2007, 45 (5) :1298-1305.
    [39] COLNOT S, DECAENS T, NIWA-KAWAKITA M, et al. Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas[J]. Proc Natl Acad Sci U S A, 2004, 101 (49) :17216-17221.
    [40] WU HC, LAY IS, SHIBU MA, et al. Zanthoxylum avicennae extract enhances GSK-3beta to attenuate beta-catenin via phosphatase 2A to block metastatic effects of HA22T cells and hepatocellular carcinoma xenografted nude mice[J]. Environ Toxicol, 2017, 32 (9) :2133-2143.
    [41] ISMAIL S, MAYAH W, BATTIA HE, et al. Plasma nuclear factor kappa B and serum peroxiredoxin 3 in early diagnosis of hepatocellular carcinoma[J]. Asian Pac J Cancer Prev, 2015, 16 (4) :1657-1663.
    [42] YANG J, FAN GH, WADZINSKI BE, et al. Protein phosphatase 2A interacts with and directly dephosphorylates Rel A[J].J Biol Chem, 2001, 276 (51) :47828-47833.
    [43] SHU G, ZHANG L, JIANG S, et al. Isoliensinine induces dephosphorylation of NF-kB p65 subunit at Ser536 via a PP2Adependent mechanism in hepatocellular carcinoma cells:Roles of impairing PP2A/I2PP2A interaction[J]. Oncotarget, 2016, 7 (26) :40285-40296.
    [44] BAEK SH. When signaling kinases meet histones and histone modifiers in the nucleus[J]. Mol Cell, 2011, 42 (3) :274-284.
    [45] ZHU X, LI D, ZHANG Z, et al. Persistent phosphorylation at specific H3 serine residues involved in chemical carcinogeninduced cell transformation[J]. Mol Carcinog, 2017, 56 (5) :1449-1460.
    [46] YANG N, EKANEM NR, SAKYI CA, et al. Hepatocellular carcinoma and microRNA:New perspectives on therapeutics and diagnostics[J]. Adv Drug Deliv Rev, 2015, 81:62-74.
    [47] RUVOLO PP. The Interplay between PP2A and microRNAs in Leukemia[J]. Front Oncol, 2015, 5:43.
    [48] CHENG Z, WANG HZ, LI X, et al. MicroRNA-184 inhibits cell proliferation and invasion, and specifically targets TNFAIP2 in Glioma[J]. J Exp Clin Cancer Res, 2015, 34:27.
    [49] ZHUANG Q, ZHOU T, HE C, et al. Protein phosphatase 2AB55delta enhances chemotherapy sensitivity of human hepatocellular carcinoma under the regulation of microRNA-133b[J]. J Exp Clin Cancer Res, 2016, 35:67.
    [50] CHRISTEN V, DUONG F, BERNSMEIER C, et al. Inhibition of alpha interferon signaling by hepatitis B virus[J]. J Virol, 2007, 81 (1) :159-165.
    [51] DUONG FH, DILL MT, MATTER MS, et al. Protein phosphatase 2A promotes hepatocellular carcinogenesis in the diethylnitrosamine mouse model through inhibition of p53[J]. Carcinogenesis, 2014, 35 (1) :114-122.
    [52] GONG SJ, FENG XJ, SONG WH, et al. Upregulation of PP2Ac predicts poor prognosis and contributes to aggressiveness in hepatocellular carcinoma[J]. Cancer Biol Ther, 2016, 17 (2) :151-162.
    [53] DUONG FH, CHRISREN V, LIN S, et al. Hepatitis C virus-induced up-regulation of protein phosphatase 2A inhibits histone modification and DNA damage repair[J]. Hepatology, 2010, 51 (3) :741-751.
    [54] DUONG FH, FILIPOWICZ M, TRIPODI M, et al. Hepatitis C virus inhibits interferon signaling through up-regulation of protein phosphatase 2A[J]. Gastroenterology, 2004, 126 (1) :263-277.
    [55] LAU CC, SUN T, CHING AK, et al. Viral-human chimeric transcript predisposes risk to liver cancer development and progression[J]. Cancer cell, 2014, 25 (3) :335-349.
    [56] FU QH, ZHANG Q, ZHANG JY, et al. LB-100 sensitizes hepatocellular carcinoma cells to the effects of sorafenib during hypoxia by activation of Smad3 phosphorylation[J].Tumour Bio, 2016, 37 (6) :7277-7286.
    [57] XU J, SHEN ZY, CHEN XG, et al. A randomized controlled trial of Licartin for preventing hepatoma recurrence after liver transplantation[J]. Hepatology, 2007, 45 (2) :269-276.
    [58] LODOLA F, LAFORENZA U, BONETTI E, et al. Store-operated Ca2+entry is remodelled and controls in vitro angiogenesis in endothelial progenitor cells isolated from tumoral patients[J]. PLo S One, 2012, 7 (9) :e42541.
    [59] TANG J, GUO YS, ZHANG Y, et al. CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma[J]. Cell Death Differ, 2012, 19 (11) :1779-1790.
    [60] TANG J, GUO YS, YU XL, et al. CD147 reinforces[Ca2+]i oscillations and promotes oncogenic progression in hepatocellular carcinoma[J]. Oncotarget, 2015, 6 (33) :34831-34845.
    [61] GILLIAM DT, MENON V, BRETZ NP, et al. The CD24 surface antigen in neural development and disease[J]. Neurobiol Dis, 2017, 99:133-144.
    [62] WAN X, CHENG C, SHAO Q, et al. CD24 promotes HCC progression via triggering Notch-related EMT and modulation of tumor microenvironment[J]. Tumour Biol, 2016, 37 (5) :6073-6084.
    [63] LU S, YAO Y, XU G, et al. CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma[J].Cell Death Dis, 2018, 9 (6) :646.
    [64] SANGODKAR J, FARRINGTON CC, MCCLINCH K, et al. All roads lead to PP2A:Exploiting the therapeutic potential of this phosphatase[J]. FEBS J, 2016, 283 (6) :1004-1024.
  • 加载中
计量
  • 文章访问数:  983
  • HTML全文浏览量:  11
  • PDF下载量:  315
  • 被引次数: 0
出版历程
  • 收稿日期:  2018-12-17
  • 出版日期:  2019-05-20
  • 分享
  • 用微信扫码二维码

    分享至好友和朋友圈

目录

    /

    返回文章
    返回