MAT2B mediates invasion and metastasis by regulating EGFR signaling pathway in hepatocellular carcinoma

  • Lijun Wu
  • Ping Chen
  • Jun Ying
  • Qi Zhang
  • Fuchen Liu
  • Bin Lv
  • Zhihui Che
  • Wenli Zhang
  • Mengmeng Wu
  • Jun Zhang
  • Dongqin YangEmail author
  • Jie LiuEmail author
Original Article


The poor prognosis of hepatocellular carcinoma (HCC) patients is mainly due to cancer metastasis. Methionine adenosyltransferase 2β (MAT2B) encodes a regulatory subunit (β) for methionine adenosyltransferase. Previous studies reveal that MAT2B provides a growth advantage for HCC, but its role in metastasis is unknown. This study showed that both in the xenograft zebra fish model and in the lung metastasis model in nude mice, the stable inhibition of MAT2B could suppress the metastasis of HCC cancer cells. Silencing of MAT2B in HCC cell lines could remarkably inhibit migration and invasion. By analysis of human phospho-kinase array membranes, we found several differentially expressed proteins, including phosphor-AKT, phospho-EGFR, phospho-Src family, phospho-FAK, phospho-STAT3 and phospho-ERK. We further confirmed the change of these EGFR pathway-related proteins was in accordance with MAT2B expression pattern through immunoblotting test. Finally, we found that MAT2B was overexpressed in HCC caner tissues and correlated with poor prognosis for HCC patients in clinical manifestation. Our study demonstrated that silencing of MAT2B could suppress liver cancer cell migration and invasion through the inhibition of EGFR signaling, which suggested that MAT2B might serve as a new prognostic marker and therapeutic target for HCC.


MAT2B Migration Invasion EGFR Hepatocellular carcinoma 


Author contributions

Lijun Wu was responsible for manuscript preparation and contributed to study design and experiment process. Ping Chen contributed to the data analysis and experiment process. Dongqin Yang contributed to study design. All co-authors contributed to the data interpretation and manuscript revision. All authors approved the final version of this manuscript.


This work was supported by grant from the National Natural Science Foundation of China ‘(81401980)’ (to Lijun Wu) and the Development Fund for Shanghai Talents ‘(201660)’ (to Dongqin Yang) and the Natural Science Foundation and Major Basic Research Program of Shanghai ‘(16JC1420104)’ (to Jie Liu).

Compliance with ethical standards

Conflict of interest

All authors have no conflicts of interest.


  1. 1.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.CrossRefGoogle Scholar
  2. 2.
    Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 2008;48:1312–27.CrossRefGoogle Scholar
  3. 3.
    Feo F, Pascale RM, Simile MM, De Miglio MR, Muroni MR, Calvisi D. Genetic alterations in liver carcinogenesis: implications for new preventive and therapeutic strategies. Crit Rev Oncog. 2000;11:19–62.CrossRefGoogle Scholar
  4. 4.
    Bosch FX, Ribes J, Díaz M, Cléries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004;127:S5–16.CrossRefGoogle Scholar
  5. 5.
    Lu SC, Mato JM. S-Adenosylmethionine in cell growth, apoptosis and liver cancer. J Gastroenterol Hepatol. 2008;23(Suppl 1):S73–7.CrossRefGoogle Scholar
  6. 6.
    Halim AB, LeGros L, Geller A, Kotb M. Expression and functional interaction of the catalytic and regulatory subunits of human methionine adenosyltransferase in mammalian cells. J Biol Chem. 1999;274:29720–5.CrossRefGoogle Scholar
  7. 7.
    Lu SC, Mato JM. S-adenosylmethionine in liver health, injury, and cancer. Physiol Rev. 2012;92:1515–42.CrossRefGoogle Scholar
  8. 8.
    Yang H, Cho ME, Li TWH, Peng H, Ko KS, Mato JM, et al. MicroRNAs regulate methionine adenosyltransferase 1A expression in hepatocellular carcinoma. J Clin Investig. 2013;123:285–98.CrossRefGoogle Scholar
  9. 9.
    Ramani K, Mato JM, Lu SC. Role of methionine adenosyltransferase genes in hepatocarcinogenesis. Cancers (Basel). 2011;3:1480–97.CrossRefGoogle Scholar
  10. 10.
    Kotb M, Mudd SH, Mato JM, Geller AM, Kredich NM, Chou JY, et al. Consensus nomenclature for the mammalian methionine adenosyltransferase genes and gene products. Trends Genet. 1997;13:51–2.CrossRefGoogle Scholar
  11. 11.
    Halim AB, LeGros L, Chamberlin ME, Geller A, Kotb M. Regulation of the human MAT2A gene encoding the catalytic alpha 2 subunit of methionine adenosyltransferase, MAT II: gene organization, promoter characterization, and identification of a site in the proximal promoter that is essential for its activity. J Biol Chem. 2001;276:9784–91.CrossRefGoogle Scholar
  12. 12.
    LeGros L, Halim AB, Chamberlin ME, Geller A, Kotb M. Regulation of the human MAT2B gene encoding the regulatory beta subunit of methionine adenosyltransferase. MAT II. J Biol Chem. 2001;276:24918–24.CrossRefGoogle Scholar
  13. 13.
    Wang Q, Liu Q, Liu Z-S, Qian Q, Sun Q, Pan D. Inhibition of hepatocelluar carcinoma MAT2A and MAT2beta gene expressions by single and dual small interfering RNA. J Exp Clin Cancer Res. 2008;27:72.CrossRefGoogle Scholar
  14. 14.
    Zhang T, Zheng Z, Liu Y, Zhang J, Zhao Y, Liu Y, et al. Overexpression of methionine adenosyltransferase II alpha (MAT2A) in gastric cancer and induction of cell cycle arrest and apoptosis in SGC-7901 cells by shRNA-mediated silencing of MAT2A gene. Acta Histochem. 2013;115:48–55.CrossRefGoogle Scholar
  15. 15.
    Liu Q, Wu K, Zhu Y, He Y, Wu J, Liu Z. Silencing MAT2A gene by RNA interference inhibited cell growth and induced apoptosis in human hepatoma cells. Hepatol Res. 2007;37:376–88.CrossRefGoogle Scholar
  16. 16.
    Ramani K, Yang H, Kuhlenkamp J, Tomasi L, Tsukamoto H, Mato JM, et al. Changes in the expression of methionine adenosyltransferase genes and S-adenosylmethionine homeostasis during hepatic stellate cell activation. Hepatology. 2010;51:986–95.Google Scholar
  17. 17.
    Martínez-Chantar ML, García-Trevijano ER, Latasa MU, Martín-Duce A, Fortes P, Caballería J, et al. Methionine adenosyltransferase II beta subunit gene expression provides a proliferative advantage in human hepatoma. Gastroenterology. 2003;124:940–8.CrossRefGoogle Scholar
  18. 18.
    Yang H, Ara AI, Magilnick N, Xia M, Ramani K, Chen H, et al. Expression pattern, regulation, and functions of methionine adenosyltransferase 2beta splicing variants in hepatoma cells. Gastroenterology. 2008;134:281–91.CrossRefGoogle Scholar
  19. 19.
    Ramani K, Yang H, Xia M, Ara AI, Mato JM, Lu SC. Leptin’s mitogenic effect in human liver cancer cells requires induction of both methionine adenosyltransferase 2A and 2beta. Hepatology. 2008;47:521–31.CrossRefGoogle Scholar
  20. 20.
    Mikol YB, Hoover KL, Creasia D, Poirier LA. Hepatocarcinogenesis in rats fed methyl-deficient, amino acid-defined diets. Carcinogenesis. 1983;4:1619–29.CrossRefGoogle Scholar
  21. 21.
    Ghoshal AK, Farber E. The induction of liver cancer by dietary deficiency of choline and methionine without added carcinogens. Carcinogenesis. 1984;5:1367–70.CrossRefGoogle Scholar
  22. 22.
    El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.CrossRefGoogle Scholar
  23. 23.
    Perry JF, Poustchi H, George J, Farrell GC, McCaughan GW, Strasser SI. Current approaches to the diagnosis and management of hepatocellular carcinoma. Clin Exp Med. 2005;5:1–13.CrossRefGoogle Scholar
  24. 24.
    Mazzoccoli G, Tarquini R, Valoriani A, Oben J, Vinciguerra M, Marra F. Management strategies for hepatocellular carcinoma: old certainties and new realities. Clin Exp Med. 2016;16:243–56.CrossRefGoogle Scholar
  25. 25.
    Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis. 2010;42(Suppl 3):S206–14.CrossRefGoogle Scholar
  26. 26.
    Wu F, Yang L-Y, Li Y-F, Ou D-P, Chen D-P, Fan C. Novel role for epidermal growth factor-like domain 7 in metastasis of human hepatocellular carcinoma. Hepatology. 2009;50:1839–50.CrossRefGoogle Scholar
  27. 27.
    Ye Q-H, Qin L-X, Forgues M, He P, Kim JW, Peng AC, et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 2003;9:416–23.CrossRefGoogle Scholar
  28. 28.
    Luedde T. MicroRNA-151 and its hosting gene FAK (focal adhesion kinase) regulate tumor cell migration and spreading of hepatocellular carcinoma. Hepatology. 2010;52:1164–6.CrossRefGoogle Scholar
  29. 29.
    Yang F, Yin Y, Wang F, Wang Y, Zhang L, Tang Y, et al. miR-17-5p Promotes migration of human hepatocellular carcinoma cells through the p38 mitogen-activated protein kinase-heat shock protein 27 pathway. Hepatology. 2010;51:1614–23.CrossRefGoogle Scholar
  30. 30.
    Zandi R, Larsen AB, Andersen P, Stockhausen M-T, Poulsen HS. Mechanisms for oncogenic activation of the epidermal growth factor receptor. Cell Signal. 2007;19:2013–23.CrossRefGoogle Scholar
  31. 31.
    Berasain C, Castillo J, Prieto J, Avila MA. New molecular targets for hepatocellular carcinoma: the ErbB1 signaling system. Liver Int. 2007;27:174–85.CrossRefGoogle Scholar
  32. 32.
    Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene. 2006;25:3787–800.CrossRefGoogle Scholar
  33. 33.
    Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7:505–16.CrossRefGoogle Scholar
  34. 34.
    Kira S, Nakanishi T, Suemori S, Kitamoto M, Watanabe Y, Kajiyama G. Expression of transforming growth factor alpha and epidermal growth factor receptor in human hepatocellular carcinoma. Liver. 1997;17:177–82.CrossRefGoogle Scholar
  35. 35.
    Daveau M, Scotte M, François A, Coulouarn C, Ros G, Tallet Y, et al. Hepatocyte growth factor, transforming growth factor alpha, and their receptors as combined markers of prognosis in hepatocellular carcinoma. Mol Carcinog. 2003;36:130–41.CrossRefGoogle Scholar
  36. 36.
    Liebmann C. EGF receptor activation by GPCRs: an universal pathway reveals different versions. Mol Cell Endocrinol. 2011;331:222–31.CrossRefGoogle Scholar
  37. 37.
    Jorissen RN, Walker F, Pouliot N, Garrett TPJ, Ward CW, Burgess AW. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res. 2003;284:31–53.CrossRefGoogle Scholar
  38. 38.
    Peng H, Dara L, Li TWH, Zheng Y, Yang H, Tomasi ML, et al. MAT2B-GIT1 interplay activates MEK1/ERK 1 and 2 to induce growth in human liver and colon cancer. Hepatology. 2013;57:2299–313.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Digestive Diseases of Huashan HosptialFudan UniversityShanghaiChina
  2. 2.Fudan University LibraryShanghaiChina
  3. 3.Institutes of Biomedical Sciences, Shanghai Medical CollegeFudan UniversityShanghaiChina
  4. 4.The Third Department of Hepatic Surgery of Eastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghaiChina

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