Skip to main content
Log in

Overexpression of MMSET is Correlation with Poor Prognosis in Hepatocellular Carcinoma

  • Research
  • Published:
Pathology & Oncology Research

Abstract

The multiple myeloma SET domain (MMSET) involved in the t(4;14)(p16;q32) chromosomal translocation encodes a histone lysine methyltransferase. High expression of MMSET is common translocation in multiple myeloma (MM) and is associated with the worst prognosis. Recent studies have shown that overexpression of MMSET is significant in other tumor types compared to their normal tissues. However, little is known about its role in hepatocellular carcinoma (HCC). In these study we investigate the expression of MMSET in HCC and to make correlations with clinicopathologic features. Twenty-eight pairs of HCC and adjacent non-tumor tissues, and eight normal liver tissues were collected for MMSET detection by western blotting and real time-PCR analysis. Immunohistochemistry was used to determine the expression of MMSET in HCC and adjacent non-tumor tissues from 103 patients. Overexpression of MMSET was significantly associated with Edmondson stage, vascular invasion. Moreover, Kaplan-Meier curves showed that MMSET upregulated was associated with shorter overall survival and disease-free survival in HCC patient. In conclusion, our study demonstrates for the first time that overexpression of MMSET is an independent prognostic factor and is correlated with poor survival in HCC patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Di Bisceglie AM (2004) Issues in screening and surveillance for hepatocellular carcinoma. Gastroenterology 127:S104–S107

    Article  PubMed  Google Scholar 

  2. Szabó E, Páska C, Kaposi Novák P, Schaff Z, Kiss A (2004) Similarities and differences in hepatitis B and C virus induced hepatocarcinogenesis. Pathol Oncol Res 10(1):5–11

    Article  PubMed  Google Scholar 

  3. El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132(7):2557–2576

    Article  PubMed  CAS  Google Scholar 

  4. Xie B, Wang DH, Spechler SJ (2012) Sorafenib for treatment of hepatocellular carcinoma: a systematic review. Dig Dis Sci 57(5):1122–1129

    Article  PubMed  CAS  Google Scholar 

  5. Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol 6(11):838–849

    Article  PubMed  CAS  Google Scholar 

  6. Li Y, Trojer P, Xu CF et al (2009) The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate. J Biol Chem 284(49):34283–34295

    Article  PubMed  CAS  Google Scholar 

  7. Stec I, Wright TJ, van Ommen GJ et al (1998) WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma. Hum Mol Genet 7(7):1071–1082

    Article  PubMed  CAS  Google Scholar 

  8. Chesi M, Nardini E, Lim RS, Smith KD, Kuehl WM, Bergsagel PL (1998) The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 92(9):3025–3034

    PubMed  CAS  Google Scholar 

  9. Keats JJ, Reiman T, Belch AR, Pilarski LM (2006) Ten years and counting: so what do we know about t(4;14)(p16;q32) multiple myeloma. Leuk Lymphoma 47(11):2289–2300

    Article  PubMed  CAS  Google Scholar 

  10. Hudlebusch HR, Skotte J, Santoni-Rugiu E et al (2011) MMSET is highly expressed and associated with aggressiveness in neuroblastoma. Cancer Res 71(12):4226–4235

    Article  PubMed  CAS  Google Scholar 

  11. Li J, Yin C, Okamoto H, Mushlin H et al (2008) Identification of a novel proliferation-related protein, WHSC1 4a, in human gliomas. Neuro Oncol 10(1):45–51

    Article  PubMed  Google Scholar 

  12. Kang HB, Choi Y, Lee JM et al (2009) The histone methyltransferase, NSD2, enhances androgen receptor-mediated transcription. FEBS Lett 583(12):1880–1886

    Article  PubMed  CAS  Google Scholar 

  13. Rhodes DR, Yu J, Shanker K et al (2004) ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6(1):1–6

    PubMed  CAS  Google Scholar 

  14. Kassambara A, Klein B, Moreaux J (2009) MMSET is overexpressed in cancers: link with tumor aggressiveness. Biochem Biophys Res Commun 379(4):840–845

    Article  PubMed  CAS  Google Scholar 

  15. Hudlebusch HR, Santoni-Rugiu E, Simon R et al (2011) The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors. Clin Cancer Res 17(9):2919–2933

    Article  PubMed  CAS  Google Scholar 

  16. Okabe H, Satoh S, Kato T et al (2001) Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. Cancer Res 61(5):2129–2137

    PubMed  CAS  Google Scholar 

  17. Lauring J, Abukhdeir AM, Konishi H et al (2008) The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity. Blood 111(2):856–864

    Article  PubMed  CAS  Google Scholar 

  18. Garlisi CG, Uss AS, Xiao H et al (2001) A unique mRNA initiated within a middle intron of WHSC1/MMSET encodes a DNA binding protein that suppresses human IL-5 transcription. Am J Respir Cell Mol Biol 24(1):90–98

    Article  PubMed  CAS  Google Scholar 

  19. Kim JY, Kee HJ, Choe NW et al (2008) Multiple-myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity. Mol Cell Biol 28(6):2023–2034

    Article  PubMed  CAS  Google Scholar 

  20. Keats JJ, Reiman T, Maxwell CA et al (2003) In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood 101(4):1520–1529

    Article  PubMed  CAS  Google Scholar 

  21. Marango J, Shimoyama M, Nishio H et al (2008) The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Blood 111(6):3145–3154

    Article  PubMed  CAS  Google Scholar 

  22. Sáez B, Martín-Subero JI, Lahortiga I et al (2007) Simultaneous translocations of FGFR3/MMSET and CCND1 into two different IGH alleles in multiple myeloma: lack of concurrent activation of both proto-oncogenes. Cancer Genet Cytogenet 175(1):65–68

    Article  PubMed  Google Scholar 

  23. Martinez-Garcia E, Popovic R et al (2011) The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood 117(1):211–220

    Article  PubMed  CAS  Google Scholar 

  24. Hudlebusch HR, Theilgaard-Mönch K, Lodahl M, Johnsen HE, Rasmussen T (2005) Identification of ID-1 as a potential target gene of MMSET in multiple myeloma. Br J Haematol 130(5):700–708

    Article  PubMed  CAS  Google Scholar 

  25. Toyokawa G, Cho HS, Masuda K et al (2011) Histone lysine methyltransferase Wolf-Hirschhorn syndrome candidate one is involved in human carcinogenesis through regulation of the Wnt pathway. Neoplasia 13(10):887–898

    PubMed  CAS  Google Scholar 

  26. Pei H, Zhang L, Luo K et al (2011) MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. Nature 470(7332):124–128

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of Interest

None

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zhi-Ming Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhou, P., Wu, LL., Wu, KM. et al. Overexpression of MMSET is Correlation with Poor Prognosis in Hepatocellular Carcinoma. Pathol. Oncol. Res. 19, 303–309 (2013). https://doi.org/10.1007/s12253-012-9583-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-012-9583-z

Keywords

Navigation