Tumor Biology

, Volume 36, Issue 11, pp 8761–8772 | Cite as

Downregulation of TRIM21 contributes to hepatocellular carcinoma carcinogenesis and indicates poor prognosis of cancers

  • Qianshan Ding
  • Du He
  • Ke He
  • Qian Zhang
  • Meng Tang
  • Jinfen Dai
  • Hanlin Lv
  • Xiaochen Wang
  • Guoan Xiang
  • Honggang Yu
Research Article

Abstract

The aim of our work is to clarify the clinical implication and functional role of tripartite motif 21 (TRIM21) in hepatocellular carcinoma (HCC). We validated that TRIM21 was downregulated in liver cancer samples by immunohistochemical (IHC) staining. We also demonstrated that its downregulation was associated with several clinicopathologic features such as tumor numbers, T stage, Barcelona Clinic Liver Cancer (BCLC) stage, and Cancer of the Liver Italian Program (CLIP) stage of HCC patients. Importantly, the expression of TRIM21 in tumor samples is significantly correlated with the prognosis of the patients. We further silenced TRIM21 in HCC cell HepG2 and LM3 and confirmed that TRIM21 silencing will promote cancer cell proliferation (CCK-8 assay), colony forming (plate colony-forming assay), migration (transwell assay), and the ability of antiapoptosis (annexin V-FITC/PI staining) in vitro. Then, we predicted gene sets influenced by TRIM21 by using bioinformatic tools. For the first time, we prove that TRIM21 is a potential tumor suppressor in HCC and its low expression indicates poor prognosis. Our findings provide useful insight into the mechanism of HCC origin and progression and offer clues to novel HCC therapies.

Keywords

TRIM21 Tumor suppressor Cancer Prognosis Hepatocellular carcinoma 

Notes

Acknowledgments

The first author would thank Liu Can from College of Chinese Language and Literature, Wuhan University for her kind encouragement. The authors also would like to thank Dr. Wang Bicheng and Dr. Zeng Zhi for the technical help on pathology. The study was supported by the Natural Science Foundation of China (No. 81272963 and No. 81172350).

Authors’ contributions

Conceived and designed the experiments: QD, HY.

Performed the experiments: QD, DH, HL, XW.

Contributed funds/reagents/materials: KH, GX, HY.

Wrote the paper: QD, QZ, MT, JD.

All authors read and approved the final manuscript.

Conflicts of interest

The authors declare that they have no competing interest.

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E. Forman D. Global Cancer Stat. 2011;61:69–90.Google Scholar
  2. 2.
    Kishi Y, Shimada K, Nara S, Esaki M, Kosuge T. Role of hepatectomy for recurrent or initially unresectable hepatocellular carcinoma. World J Hepatol. 2014;6:836–43.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ikeda K, Inoue S. TRIM proteins as RING finger E3 ubiquitin ligases. Adv Exp Med Biol. 2012;770:27–37.CrossRefPubMedGoogle Scholar
  4. 4.
    Schwamborn JC, Berezikov E, Knoblich JA. The TRIM-NHL protein TRIM32 activates microRNAs and prevents self-renewal in mouse neural progenitors. Cell. 2009;136:913–25.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Uchil PD, Pawliczek T, Reynolds TD, Ding S, Hinz A, Munro JB, et al. TRIM15 is a focal adhesion protein that regulates focal adhesion disassembly. J Cell Sci. 2014;127:3928–42.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Cambiaghi V, Giuliani V, Lombardi S, Marinelli C, Toffalorio F, Pelicci PG. TRIM proteins in cancer. Adv Exp Med Biol. 2012;770:77–91.CrossRefPubMedGoogle Scholar
  7. 7.
    Kawai T, Akira S. Regulation of innate immune signalling pathways by the tripartite motif (TRIM) family proteins. EMBO Mol Med. 2011;3:513–27.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Petrera F, Meroni G. TRIM proteins in development. Adv Exp Med Biol. 2012;770:131–41.CrossRefPubMedGoogle Scholar
  9. 9.
    Kanno Y, Watanabe M, Kimura T, Nonomura K, Tanaka S, Hatakeyama S. TRIM29 as a novel prostate basal cell marker for diagnosis of prostate cancer. Acta Histochem. 2014;116:708–12.CrossRefPubMedGoogle Scholar
  10. 10.
    Bell JL, Malyukova A, Kavallaris M, Marshall GM, Cheung BB. TRIM16 inhibits neuroblastoma cell proliferation through cell cycle regulation and dynamic nuclear localization. Cell Cycle. 2013;12:889–98.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Liu Y, Raheja R, Yeh N, Ciznadija D, Pedraza AM, Ozawa T, et al. TRIM3, a tumor suppressor linked to regulation of p21 (Waf1/Cip1). Oncogene. 2014;33:308–15.CrossRefPubMedGoogle Scholar
  12. 12.
    Reddy BA, van der Knaap JA, Bot AG, Mohd-Sarip A, Dekkers DH, Timmermans MA, et al. Nucleotide biosynthetic enzyme GMP synthase is a TRIM21-controlled relay of p53 stabilization. Mol Cell. 2014;53:458–70.CrossRefPubMedGoogle Scholar
  13. 13.
    McEwan WA, James LC. TRIM21-dependent intracellular antibody neutralization of virus infection. Prog Mol Biol Transl Sci. 2015;129:167–87.CrossRefPubMedGoogle Scholar
  14. 14.
    Kyriakidis NC, Kapsogeorgou EK, Gourzi VC, Konsta OD, Baltatzis GE, Tzioufas AG. Toll-like receptor 3 stimulation promotes Ro52/TRIM21 synthesis and nuclear redistribution in salivary gland epithelial cells, partially via type I interferon pathway. Clin Exp Immunol. 2014;178:548–60.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Young JA, Sermwittayawong D, Kim HJ, Nandu S, An N, Erdjument-Bromage H, et al. Fas-associated death domain (FADD) and the E3 ubiquitin-protein ligase TRIM21 interact to negatively regulate virus-induced interferon production. J Biol Chem. 2011;286:6521–31.CrossRefPubMedGoogle Scholar
  16. 16.
    Espinosa A, Zhou W, Ek M, Hedlund M, Brauner S, Popovic K, et al. The Sjogren’s syndrome-associated autoantigen Ro52 is an E3 ligase that regulates proliferation and cell death. J Immunol. 2006;176:6277–85.CrossRefPubMedGoogle Scholar
  17. 17.
    Roessler S, Jia HL, Budhu A, Forgues M, Ye QH, Lee JS, et al. A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients. Cancer Res. 2010;70:10202–12.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Marisa L, de Reyniès A, Duval A, Selves J, Gaub MP, Vescovo L, et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med. 2013;10:e1001453.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Rousseaux S, Debernardi A, Jacquiau B, Vitte AL, Vesin A, Nagy-Mignotte H, et al. Ectopic activation of germline and placental genes identifies aggressive metastasis-prone lung cancers. Sci Transl Med. 2013;5:186ra66.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Menéndez A, Gómez J, Escanlar E, Caminal-Montero L, Mozo L. Clinical associations of anti-SSA/Ro60 and anti-Ro52/TRIM21 antibodies: Diagnostic utility of their separate detection. Autoimmunity. 2013;46:32–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Oke V, Wahren-Herlenius M. The immunobiology of Ro52 (TRIM21) in autoimmunity: a critical review. J Autoimmun. 2012;39:77–82.CrossRefPubMedGoogle Scholar
  22. 22.
    Vaysburd M, Watkinson RE, Cooper H, Reed M, O’Connell K, Smith J, et al. Intracellular antibody receptor TRIM21 prevents fatal viral infection. Proc Natl Acad Sci U S A. 2013;110:12397–401.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Higgs R, Ní Gabhann J, Ben Larbi N, Breen EP, Fitzgerald KA, Jefferies CA. The E3 ubiquitin ligase Ro52 negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. J Immunol. 2008;181:1780–6.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    McEwan WA, Tam JC, Watkinson RE, Bidgood SR, Mallery DL, James LC. Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21. Nat Immunol. 2013;14:327–36.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lee OH, Lee J, Lee KH, Woo YM, Kang JH, Yoon HG, et al. Role of the focal adhesion protein TRIM15 in colon cancer development. Biochim Biophys Acta. 1853;2015:409–21.Google Scholar
  26. 26.
    Chen N, Balasenthil S, Reuther J, Killary AM. DEAR1, a novel tumor suppressor that regulates cell polarity and epithelial plasticity. Cancer Res. 2014;74:5683–9.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Quintás-Cardama A, Post SM, Solis LM, Xiong S, Yang P, Chen N, et al. Loss of the novel tumour suppressor and polarity gene Trim62 (Dear1) synergizes with oncogenic Ras in invasive lung cancer. J Pathol. 2014;234:108–19.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Jia D, Wei L, Guo W, Zha R, Bao M, Chen Z, et al. Genome-wide copy number analyses identified novel cancer genes in hepatocellular carcinoma. Hepatology. 2011;54:1227–36.CrossRefPubMedGoogle Scholar
  29. 29.
    Herquel B, Ouararhni K, Khetchoumian K, Ignat M, Teletin M, Mark M, et al. Transcription cofactors TRIM24, TRIM28, and TRIM33 associate to form regulatory complexes that suppress murine hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2011;108:8212–7.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Jauharoh SN, Saegusa J, Sugimoto T, Ardianto B, Kasagi S, Sugiyama D, et al. SS-A/Ro52 promotes apoptosis by regulating Bcl-2 production. Biochem Biophys Res Commun. 2012;417:582–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Zhang J, Fang L, Zhu X, Qiao Y, Yu M, Wang L, et al. Ro52/SSA sensitizes cells to death receptor-induced apoptosis by down-regulating c-FLIP (L). Cell Biol Int. 2012;36:463–8.CrossRefPubMedGoogle Scholar
  32. 32.
    He P, Tang ZY, Ye SL, Liu BB, Liu YK. The targeted expression of interleukin-2 in human hepatocellular carcinoma cells. J Exp Clin Cancer Res. 2000;19:183–7.PubMedGoogle Scholar
  33. 33.
    Palmieri G, Montella L, Milo M, Fiore R, Biondi E, Bianco AR, et al. Ultra-low dose interleukin-2 in unresectable hepatocellular carcinoma. Am J Clin Oncol. 2002;25:224–6.CrossRefPubMedGoogle Scholar
  34. 34.
    Ikeguchi M, Hirooka Y. Interleukin-2 gene expression is a new biological prognostic marker in hepatocellular carcinomas. Onkologie. 2005;28:255–9.PubMedGoogle Scholar
  35. 35.
    Ishii T, Ohnuma K, Murakami A, Takasawa N, Yamochi T, Iwata S, et al. SS-A/Ro52, an autoantigen involved in CD28-mediated IL-2 production. J Immunol. 2003;170:3653–61.CrossRefPubMedGoogle Scholar
  36. 36.
    Wada K, Niida M, Tanaka M, Kamitani T. Ro52-mediated monoubiquitination of IKKβ down-regulates NF-kB signalling. J Biochem. 2009;146:821–32.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Erstad DJ, Cusack Jr JC. Targeting the NF-κB pathway in cancer therapy. Surg Oncol Clin N Am. 2013;22:705–46.CrossRefPubMedGoogle Scholar
  38. 38.
    Zheng T, Hong X, Wang J, Pei T, Liang Y, Yin D, et al. Gankyrin promotes tumor growth and metastasis through activation of IL-6/STAT3 signaling in human cholangiocarcinoma. Hepatology. 2014;59:935–46.CrossRefPubMedGoogle Scholar
  39. 39.
    Kim YC, Cao Y, Pitterle DM, O’Briant KC, Bepler G. SSA/RO52gene and expressed sequence tags in an 85 kb region of chromosome segment 11p15.5. Int J Cancer. 2000;87:61–7.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Qianshan Ding
    • 1
  • Du He
    • 2
  • Ke He
    • 3
  • Qian Zhang
    • 4
  • Meng Tang
    • 4
  • Jinfen Dai
    • 1
  • Hanlin Lv
    • 5
  • Xiaochen Wang
    • 5
  • Guoan Xiang
    • 3
  • Honggang Yu
    • 6
  1. 1.Department of GastroenterologyRenmin Hospital of Wuhan UniversityWuhanChina
  2. 2.Department of Oncology, The Central Hospital of Enshi Autonomous of PrefectureEnshi Clinical College of Wuhan UniversityEnshiChina
  3. 3.Department of General Surgery, The Second People’s Hospital of Guangdong ProvinceSouthern Medical UniversityGuangzhouChina
  4. 4.Department of Immunology, School of Basic MedicineWuhan UniversityWuhanChina
  5. 5.Central LaboratoryRenmin Hospital of Wuhan UnviersityWuhanChina
  6. 6.Department of Gastroenterology, Renmin Hospital of Wuhan University, Institute for Gastroenterology and HepatologyWuhan UniversityWuhanChina

Personalised recommendations