Tumor Biology

, Volume 37, Issue 12, pp 16269–16274 | Cite as

Tissue transglutaminase 2 exerts a tumor-promoting role in hepatitis B virus-related hepatocellular carcinoma

  • Chengbo Yu
  • Qing Cao
  • Ping Chen
  • Shigui Yang
  • Xianli Gong
  • Min Deng
  • Bing Ruan
  • Lanjuan Li
Original Article

Abstract

Hepatitis B virus (HBV) infection is a major risk factor which can lead to development of hepatocellular carcinoma (HCC). Tissue transglutaminase-2 (TG2) has been shown to be critical for cancer progression. However, how TG2 promotes the progression of HBV-related HCC remains unknown. In this study, we aimed to explore the expression and function of TG2 on HBV-related HCC progression. The expression levels of TG2 were examined in a series of HBV-related HCC tissues and a panel of HCC cell lines. The effects of TG2 knockdown on the proliferation and migration of HBV-related cells were determined. TG2 expression was found to be significantly upregulated in HBV-related HCC tissues. TG2 expression was higher in HBV-related HCC cell lines than HBV-unrelated HCC cell lines. Moreover, inhibition of TG2 in HCC cell lines HepG2.2.15 and Hep3B could inhibit cell proliferation, migration, and invasion in vitro. Our results indicated that TG2 could serve as a promising target for treatment of HBV-related HCC patients.

Keywords

HBV-related HCC TG2 Marker Targeted therapy, metastasis 

Notes

Acknowledgments

The work was supported by grants from the National Scientific and Technological Major Project of China (No.2013ZX10004904).

Compliance with ethical standards

For the use of these clinical materials for research purposes, prior patient consent and approval from the Institutional Research Ethics Committee of The First Affiliated Hospital, Zhejiang University School of Medicine were obtained.

References

  1. 1.
    El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7):2557–76.CrossRefPubMedGoogle Scholar
  2. 2.
    Xu C, Zhou W, Wang Y, Qiao L, Hepatitis B. Virus-induced hepatocellular carcinoma. Cancer Lett. 2014;345(2):216–22.CrossRefPubMedGoogle Scholar
  3. 3.
    Su IJ, Wang HC, Wu HC, Huang WY. Ground glass hepatocytes contain pre-S mutants and represent preneoplastic lesions in chronic hepatitis B virus infection. J Gastroenterol Hepatol. 2008;23(8 Pt 1):1169–74.CrossRefPubMedGoogle Scholar
  4. 4.
    Kew MC, Hepatitis B. Virus x protein in the pathogenesis of hepatitis B virus-induced hepatocellular carcinoma. J Gastroenterol Hepatol. 2011;26(Suppl 1):144–52.CrossRefPubMedGoogle Scholar
  5. 5.
    Assi J, Srivastava G, Matta A, Chang MC, Walfish PG, Ralhan R. Transglutaminase 2 overexpression in tumor stroma identifies invasive ductal carcinomas of breast at high risk of recurrence. PLoS One. 2013;8:e74437.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Cellura D, Pickard K, Quaratino S, et al. miR-19-mediated inhibition of transglutaminase-2 leads to enhanced invasion and metastasis in colorectal cancer. Mol Cancer Res. 2015;13(7):1095–105.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Raoul JL. Natural history of hepatocellular carcinoma and current treatment options. Semin Nucl Med. 2008;38:S13–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Chen L, Ho DW, Lee NP, Sun S, Lam B, Wong KF, Yi X, Lau GK, Ng EW, Poon TC, Lai PB, Cai Z, Peng J, Leng X, Poon RT, Luk JM. Enhanced detection of early hepatocellular carcinoma by serum SELDI-TOF proteomic signature combined with alpha-fetoprotein marker. Ann Surg Oncol. 2010;17:2518–25.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Klock C, Diraimondo TR, Khosla C. Role of transglutaminase 2 in celiac disease pathogenesis. Semin Immunopathol. 2012;34:513–22.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Verma A, Guha S, Diagaradjane P, Kunnumakkara AB, Sanguino AM, Lopez-Berestein G, Sood AK, Aggarwal BB, Krishnan S, Gelovani JG, Mehta K. Therapeutic significance of elevated tissue transglutaminase expression in pancreatic cancer. Clinical cancer research: an official journal of the American Association for Cancer Research. 2008;14:2476–83.CrossRefGoogle Scholar
  11. 11.
    Kotsakis P, Wang Z, Collighan RJ, Griffin M. The role of tissue transglutaminase (TG2) in regulating the tumour progression of the mouse colon carcinoma CT26. Amino Acids. 2011;41:909–21.CrossRefPubMedGoogle Scholar
  12. 12.
    Ashour AA, Gurbuz N, Alpay SN, Abdel-Aziz AA, Mansour AM, Huo L, Ozpolat B. Elongation factor-2 kinase regulates TG2/beta1 integrin/Src/uPAR pathway and epithelial-mesenchymal transition mediating pancreatic cancer cells invasion. J Cell Mol Med. 2014;18:2235–51.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kumar S, Donti TR, Agnihotri N, Mehta K. Transglutaminase 2 reprogramming of glucose metabolism in mammary epithelial cells via activation of inflammatory signaling pathways. International journal of cancer Journal international du cancer. 2014;134:2798–807.CrossRefPubMedGoogle Scholar
  14. 14.
    Huang L, Xu AM, Liu W. Transglutaminase 2 in cancer. Am J Cancer Res. 2015;5:2756–76.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Sun Y, Mi W, Cai J, Ying W, Liu F, Lu H, Qiao Y, Jia W, Bi X, Lu N, Liu S, Qian X, Zhao X. Quantitative proteomic signature of liver cancer cells: tissue transglutaminase 2 could be a novel protein candidate of human hepatocellular carcinoma. J Proteome Res. 2008;7:3847–59.CrossRefPubMedGoogle Scholar
  16. 16.
    Wang X, Yu Z, Zhou Q, Wu X, Chen X, Li J, Zhu Z, Liu B, Su L. Tissue transglutaminase-2 promotes gastric cancer progression via the ERK1/2 pathway. Oncotarget. 2016;7:7066–79.PubMedPubMedCentralGoogle Scholar
  17. 17.
    K.D. Brown, Transglutaminase 2 and NF-kappaB: an odd couple that shapes breast cancer phenotype. Breast cancer research and treatment. 137, 329–336 (2013)Google Scholar
  18. 18.
    Wang Y, Ande SR, Mishra S. Phosphorylation of transglutaminase 2 (TG2) at serine-216 has a role in TG2 mediated activation of nuclear factor-kappa B and in the downregulation of PTEN. BMC Cancer. 2012;12:277.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Chengbo Yu
    • 1
  • Qing Cao
    • 1
  • Ping Chen
    • 1
  • Shigui Yang
    • 1
  • Xianli Gong
    • 2
  • Min Deng
    • 1
  • Bing Ruan
    • 1
  • Lanjuan Li
    • 1
  1. 1.State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of MedicineZhejiang University School of MedicineHangzhouChina
  2. 2.Department of Radiation Oncology, The First Affiliated Hospital, College of MedicineZhejiang UniversityHangzhouChina

Personalised recommendations