Back
 ENG  Vol.13 No.4 , April 2021
HBV Infection Promotes the Occurrence and Development of Hepatocellular Carcinoma through Impairing the Inhibitory Effect of PPP2R5A on MAPK/AKT/WNT Signaling Pathway
Abstract: Reversible phosphorylation and dephosphorylation play important roles in cell function and cell signal transduction. PPP2R5A (protein phosphatase 2 regulatory subunit B’ alpha) is responsible for specifically regulating the catalytic function, substrate specificity and intracellular localization of the tumor suppressor phosphatase PP2A (serine/threonine protein phosphatase 2A). Therefore, the abnormal expression and function of PPP2R5A may be related to canceration. The aim of this study was to reveal its role in the occurrence and development of hepatocellular carcinoma (HCC). It is hoped that the results of this study can provide guidance for the prevention and treatment of HCC. The results showed that PPP2R5A inhibited the proliferation and metastasis of HCC cells, and acted as a tumor suppressor in HCC cells, but it had no significant effect on cell cycle. Further research found that PPP2R5A exerted tumor suppressor efficacy by inhibiting the MAPK/AKT/WNT signaling pathway. Combined with analysis of clinical tissue samples and TCGA database, it was found that the expression of PPP2R5A in tumor tissues of Chinese HCC patients was down-regulated and significantly correlated with the progression-free survival (PFS) of HCC patients. On the contrary, PPP2R5A showed an up-regulation trend in HCC cases in TCGA database although its effect on PFS was the same with that in Chinese HCC patients. Hepatitis B virus (HBV) infection is the main pathogenic factor of HCC in China. It was found that HBV infection reduced the content of PPP2R5A in cells. It was concluded that HBV inhibited the initiation of the protective mechanism mediated by PPP2R5A, making the occurrence and progress of HCC more “unimpeded”. This conclusion will further reveal the role of PPP2R5A in HBV-induced and HBV-unrelated HCC, therefore, providing clues for the prevention and treatment of the two types of HCC, respectively.
Cite this paper: Lin, X. , Mao, Z. , Zhang, Q. , Chen, L. , Qian, H. , Liu, C. and Su, C. (2021) HBV Infection Promotes the Occurrence and Development of Hepatocellular Carcinoma through Impairing the Inhibitory Effect of PPP2R5A on MAPK/AKT/WNT Signaling Pathway. Engineering, 13, 197-214. doi: 10.4236/eng.2021.134015.
References

[1]   Xie, D.Y., Ren, Z.G., Zhou, J., Fan, J. and Gao, Q. (2020) Chinese Clinical Guidelines for the Management of Hepatocellular Carcinoma: Updates and Insights. Hepatobiliary Surgery and Nutrition, 9, 452-463.
https://doi.org/10.21037/hbsn-20-480

[2]   Jia, L., Gao, Y., He, Y., Hooper, J.D. and Yang, P. (2020) HBV Induced Hepatocellular Carcinoma and Related Potential Immunotherapy. Pharmacological Research, 159, Article ID: 104992.
https://doi.org/10.1016/j.phrs.2020.104992

[3]   Liu, S., Zhou, B., Valdes, J.D., Sun, J. and Guo, H. (2019) Serum Hepatitis B Virus RNA: A New Potential Biomarker for Chronic Hepatitis B Virus Infection. Hepatology, 69, 1816-1827.
https://doi.org/10.1002/hep.30325

[4]   Sangodkar, J., Farrington, C.C., McClinch, K., Galsky, M.D., Kastrinsky, D.B. and Narla, G. (2016) All Roads Lead to PP2A: Exploiting the Therapeutic Potential of This Phosphatase. The FEBS Journal, 283, 1004-1024.
https://doi.org/10.1111/febs.13573

[5]   Virshup, D.M. and Shenolikar, S. (2009) From Promiscuity to Precision: Protein Phosphatases Get a Makeover. Molecular Cell, 33, 537-545.
https://doi.org/10.1016/j.molcel.2009.02.015

[6]   Wlodarchak, N. and Xing, Y. (2016) PP2A as a Master Regulator of the Cell Cycle. Critical Reviews in Biochemistry and Molecular Biology, 51, 162-184.
https://doi.org/10.3109/10409238.2016.1143913

[7]   Fowle, H., Zhao, Z. and Graña, X. (2019) PP2A Holoenzymes, Substrate Specificity Driving Cellular Functions and Deregulation in Cancer. Advances in Cancer Research, 144, 55-93.
https://doi.org/10.1016/bs.acr.2019.03.009

[8]   Clark, A.R. and Ohlmeyer, M. (2019) Protein Phosphatase 2A as a Therapeutic Target in Inflammation and Neurodegeneration. Pharmacology & Therapeutics, 201, 181-201.
https://doi.org/10.1016/j.pharmthera.2019.05.016

[9]   Bao, Y., Oguz, G., Lee, W.C., Lee, P.L., Ghosh, K., Li, J., et al. (2020) EZH2-Mediated PP2A Inactivation Confers Resistance to HER2-Targeted Breast Cancer Therapy. Nature Communications, 11, Article No. 5878.
https://doi.org/10.1038/s41467-020-19704-x

[10]   Liu, Z., Yoshimi, A., Wang, J., Cho, H., Lee, S.C.-W., Ki, M., et al. (2020) Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization. Cancer Discovery, 10, 806-821.
https://doi.org/10.1158/2159-8290.CD-19-1330

[11]   Silverstein, A.M., Barrow, C.A., Davis, A.J. and Mumby, M.C. (2002) Actions of PP2A on the MAP Kinase Pathway and Apoptosis Are Mediated by Distinct Regulatory Subunits. Proceedings of the National Academy of Sciences of the United States of America, 99, 4221-4226.
https://doi.org/10.1073/pnas.072071699

[12]   Rodriguez Pino, M., Castillo, B., Kim, B. and Kim, L.W. (2015) PP2A/B56 and GSK3/Ras Suppress PKB Activity during Dictyostelium chemotaxis. Molecular Biology of the Cell, 26, 4347-4357.
https://doi.org/10.1091/mbc.E14-06-1130

[13]   Kauko, O. and Westermarck, J. (2018) Non-Genomic Mechanisms of Protein Phosphatase 2A (PP2A) Regulation in Cancer. The International Journal of Biochemistry & Cell Biology, 96, 157-164.
https://doi.org/10.1016/j.biocel.2018.01.005

[14]   Zhuang, Z., Hu, F., Hu, J., Wang, C., Hou, J., Yu, Z., et al. (2017) MicroRNA-218 Promotes Cisplatin Resistance in Oral Cancer via the PPP2R5A/Wnt Signaling Pathway. Oncology Reports, 38, 2051-2061.
https://doi.org/10.3892/or.2017.5899

[15]   Forbes, S.A., Tang, G., Bindal, N., Bamford, S., Dawson, E., Cole, C., et al. (2010) COSMIC (The Catalogue of Somatic Mutations in Cancer): A Resource to Investigate Acquired Mutations in Human Cancer. Nucleic Acids Research, 38, D652-D657.
https://doi.org/10.1093/nar/gkp995

[16]   Kirchhefer, U., Heinick, A., König, S., Kristensen, T., Müller, F.U., Seidl, M.D., et al. (2014) Protein Phosphatase 2A Is Regulated by Protein Kinase Cα (PKCα)-Dependent Phosphorylation of Its Targeting Subunit B56α at Ser41. Journal of Biological Chemistry, 289, 163-176.
https://doi.org/10.1074/jbc.M113.507996

[17]   Giannakis, M., Hodis, E., Mu, J.X., Yamauchi, M., Rosenbluh, J., Cibulskis, K., et al. (2014) RNF43 Is Frequently Mutated in Colorectal and Endometrial Cancers. Nature Genetics, 46, 1264-1266.
https://doi.org/10.1038/ng.3127

[18]   DeGrande, S.T., Little, S.C., Nixon, D.J., Wright, P., Snyder, J., Dun, W., et al. (2013) Molecular Mechanisms Underlying Cardiac Protein Phosphatase 2A Regulation in Heart. Journal of Biological Chemistry, 288, 1032-1046.
https://doi.org/10.1074/jbc.M112.426957

[19]   Greenwood, E.J., Matheson, N.J., Wals, K., van den Boomen, D.J., Antrobus, R., Williamson, J.C., et al. (2016) Temporal Proteomic Analysis of HIV Infection Reveals Remodelling of the Host Phosphoproteome by Lentiviral Vif Variants. Elife, 5, e18296.
https://doi.org/10.7554/eLife.18296

[20]   Liu, J.F., Chen, P.C., Chang, T.M. and Hou, C.H. (2020) Monocyte Chemoattractant Protein-1 Promotes Cancer Cell Migration via c-Raf/MAPK/AP-1 Pathway and MMP-9 Production in Osteosarcoma. Journal of Experimental & Clinical Cancer Research, 39, Article No. 254.
https://doi.org/10.1186/s13046-020-01756-y

[21]   Wu, S., Chen, M., Huang, J., Zhang, F., Lv, Z., Jia, Y., et al. (2020) ORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis through PI3K/Akt Signaling and MAPK-Dependent Focal Adhesion Disassembly. Cancer Research, 81, 986-1000.
https://doi.org/10.1158/0008-5472.CAN-20-0049

[22]   Zuo, Q., He, J., Zhang, S., Wang, H., Jin, G., Jin, H., et al. (2021) PPARγ Coactivator-1α Suppresses Metastasis of Hepatocellular Carcinoma by Inhibiting Warburg Effect by PPARγ-Dependent WNT/β-Catenin/Pyruvate Dehydrogenase Kinase Isozyme 1 Axis. Hepatology, 73, 644-660.
https://doi.org/10.1002/hep.31280

[23]   Pan, J., Fang, S., Tian, H., Zhou, C., Zhao, X., Tian, H., et al. (2020) lncRNA JPX/miR-33a-5p/Twist1 axis Regulates Tumorigenesis and Metastasis of Lung Cancer by Activating Wnt/β-Catenin Signaling. Molecular Cancer, 19, Article No. 9.
https://doi.org/10.1186/s12943-020-1133-9

[24]   Arnold, H.K. and Sears, R.C. (2008) A Tumor Suppressor Role for PP2A-B56alpha through Negative Regulation of c-Myc and Other Key Oncoproteins. Cancer and Metastasis Reviews, 27, 147-158.
https://doi.org/10.1007/s10555-008-9128-9

[25]   Lee, N.S., Veeranki, S., Kim, B. and Kim, L. (2008) The Function of PP2A/B56 in Non-Metazoan Multicellular Development. Differentiation, 76, 1104-1110.
https://doi.org/10.1111/j.1432-0436.2008.00301.x

[26]   Yamamoto, H., Hinoi, T., Michiue, T., Fukui, A., Usui, H., Janssens, V., et al. (2001) Inhibition of the Wnt Signaling Pathway by the PR61 Subunit of Protein Phosphatase 2A. Journal of Biological Chemistry, 276, 26875-26882.
https://doi.org/10.1074/jbc.M100443200

[27]   Ruvolo, P.P., Clark, W., Mumby, M., Gao, F. and May, W.S. (2002) A Functional role for the B56 Alpha-Subunit of Protein Phosphatase 2A in Ceramide-Mediated Regulation of Bcl2 Phosphorylation Status and Function. Journal of Biological Chemistry, 277, 22847-22852.
https://doi.org/10.1074/jbc.M201830200

[28]   Xu, Z. and Williams, B.R. (2000) The B56α Regulatory Subunit of Protein Phosphatase 2A Is a Target for Regulation by Double-Stranded RNA-Dependent Protein Kinase PKR. Molecular and Cellular Biology, 20, 5285-5299.
https://doi.org/10.1128/MCB.20.14.5285-5299.2000

[29]   Dixit, U., Pandey, A.K., Mishra, P., Sengupta, A. and Pandey, V.N. (2016) Staufen1 Promotes HCV Replication by Inhibiting Protein Kinase R and Transporting Viral RNA to the Site of Translation and Replication in the Cells. Nucleic Acids Research, 44, 5271-5287.
https://doi.org/10.1093/nar/gkw312

[30]   Malim, M.H. and Bieniasz, P.D. (2012) HIV Restriction Factors and Mechanisms of Evasion. Cold Spring Harbor Perspectives in Medicine, 2, Article ID: a006940.
https://doi.org/10.1101/cshperspect.a006940

 
 
Top