Tumor Biology

, Volume 35, Issue 10, pp 10267–10273 | Cite as

Interaction of PTPRO and TLR4 signaling in hepatocellular carcinoma

  • Donghua Xu
  • Xiaochen Wang
  • Shushan Yan
  • Yin Yin
  • Jiajie Hou
  • Xuehao Wang
  • Beicheng Sun
Research Article


Protein tyrosine phosphatase receptor type O (PTPRO) has been identified as a tumor suppressor in a number of cancers including hepatocellular carcinoma (HCC). Toll-like receptor 4 (TLR4) plays diverse roles in HCC tumorigenesis and progression. The association between PTPRO and TLR4 signaling in HCC remains largely unknown. We aimed to clarify the interaction between PTPRO and TLR4 in HCC. Surprisingly, we found reduced and positive-related expression of TLR4 and PTPRO in 84 human HCC specimens. Increased TLR4 expression and activity was found in PTPRO-overexpressed HCC cells stimulated with lipopolysaccharide (LPS). The feedback regulation of PTPRO and TLR4 was dependent on nuclear factor-κB (NF-κB) activation, as suggested by NF-κB inhibition and luciferase reporter assay. Our study suggests that the effect of PTPRO on TLR4 signaling is dependent on NF-κB pathway, suggesting an interesting PTPRO/TLR4/NF-κB signaling feedback loop in HCC carcinogenesis and progression.


Protein tyrosine phosphatase receptor type O Toll-like receptor 4 Hepatocellular carcinoma NF-κB 



This work was supported by grants from the National Natural Science Foundation for Distinguished Young Scholars (81225017) and the National Natural Science Foundation (81072029 and 91029721). This work also supported in part by the program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU and the Priority Academic Program of Jiangsu Higher Education Institutions.

Conflict of interest



  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Sun B, Karin M. Inflammation and liver tumorigenesis. Front Med. 2013;7:242–54.CrossRefPubMedGoogle Scholar
  3. 3.
    Kim DY, Han KH. Epidemiology and surveillance of hepatocellular carcinoma. Liver Cancer. 2012;1:2–14.PubMedCentralCrossRefGoogle Scholar
  4. 4.
    Szabo G, Dolganiuc A, Mandrekar P. Pattern recognition receptors: a contemporary view on liver diseases. Hepatology. 2006;44:287–98.CrossRefPubMedGoogle Scholar
  5. 5.
    Matijevic T, Pavelic J. Toll-like receptors: cost or benefit for cancer? Curr Pharm Des. 2010;16:1081–90.CrossRefPubMedGoogle Scholar
  6. 6.
    Yu LX, Yan HX, Liu Q, Yang W, Wu HP, Dong W, et al. Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology. 2010;52:1322–33.CrossRefPubMedGoogle Scholar
  7. 7.
    Huang B, Zhao J, Unkeless JC, Feng ZH, Xiong H. TLR signaling by tumor and immune cells: a double-edged sword. Oncogene. 2008;27:218–24.CrossRefPubMedGoogle Scholar
  8. 8.
    Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317:121–4.CrossRefPubMedGoogle Scholar
  9. 9.
    Wang Z, Yan J, Lin H, Hua F, Wang X, Liu H, et al. Toll-like receptor 4 activity protects against hepatocellular tumorigenesis and progression by regulating expression of DNA repair protein Ku70 in mice. Hepatology. 2013;57:1869–81.CrossRefPubMedGoogle Scholar
  10. 10.
    Hou J, Xu J, Jiang R, Wang Y, Chen C, Deng L, et al. Estrogen-sensitive PTPRO expression represses hepatocellular carcinoma progression by control of STAT3. Hepatology. 2013;57:678–88.CrossRefPubMedGoogle Scholar
  11. 11.
    Motiwala T, Kutay H, Ghoshal K, Bai S, Seimiya H, Tsuruo T, et al. Protein tyrosine phosphatase receptor-type O (PTPRO) exhibits characteristics of a candidate tumor suppressor in human lung cancer. Proc Natl Acad Sci U S A. 2004;101:13844–9.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Huang YT, Li FF, Ke C, Li Z, Li ZT, Zou XF, et al. PTPRO promoter methylation is predictive of poorer outcome for HER2-positive breast cancer: indication for personalized therapy. J Transl Med. 2013;11:245.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Fukata M, Abreu MT. Role of Toll-like receptors in gastrointestinal malignancies. Oncogene. 2008;27:234–43.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Wei XQ, Guo YW, Liu JJ, Wen ZF, Yang SJ, Yao JL. The significance of toll-like receptor 4 (TLR4) expression in patients with chronic hepatitis B. Clin Invest Med. 2008;31:E123–30.PubMedGoogle Scholar
  15. 15.
    Wang JP, Zhang Y, Wei X, Li J, Nan XP, Yu HT, et al. Circulating toll-like receptor (TLR) 2, TLR4, and regulatory T cells in patients with chronic hepatitis C. APMIS. 2010;118:261–70.CrossRefPubMedGoogle Scholar
  16. 16.
    Machida K, Tsukamoto H, Mkrtchyan H, Duan L, Dynnyk A, Liu HM, et al. Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog. Proc Natl Acad Sci U S A. 2009;106:1548–53.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human toll-like receptors and related genes. Biol Pharm Bull. 2005;28:886–92.CrossRefPubMedGoogle Scholar
  18. 18.
    Bauer AK, Dixon D, DeGraff LM, Cho HY, Walker CR, Malkinson AM, et al. Toll-like receptor 4 in butylated hydroxytoluene-induced mouse pulmonary inflammation and tumorigenesis. J Natl Cancer Inst. 2005;97:1778–81.CrossRefPubMedGoogle Scholar
  19. 19.
    Mai CW, Kang YB, Pichika MR. Should a toll-like receptor 4 (TLR-4) agonist or antagonist be designed to treat cancer? TLR-4: its expression and effects in the ten most common cancers. Oncol Targets Ther. 2013;6:1573–87.Google Scholar
  20. 20.
    Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. 2012;21:504–16.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Alonso A, Sasin J, Bottini N, Friedberg I, Osterman A, Godzik A, et al. Protein tyrosine phosphatases in the human genome. Cell. 2004;117:699–711.CrossRefPubMedGoogle Scholar
  22. 22.
    Motiwala T, Majumder S, Kutay H, Smith DS, Neuberg DS, Lucas DM, et al. Methylation and silencing of protein tyrosine phosphatase receptor type O in chronic lymphocytic leukemia. Clin Cancer Res. 2007;13:3174–81.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Chen L, Juszczynski P, Takeyama K, Aguiar RC, Shipp MA. Protein tyrosine phosphatase receptor-type O truncated (PTPROt) regulates SYK phosphorylation, proximal B-cell-receptor signaling, and cellular proliferation. Blood. 2006;108:3428–33.CrossRefPubMedGoogle Scholar
  24. 24.
    Calvisi DF, Ladu S, Gorden A, Farina M, Lee JS, Conner EA, et al. Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. J Clin Invest. 2007;117:2713–22.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Hou J, Xia Y, Jiang R, Chen D, Xu J, Deng L, et al. PTPRO plays a dual role in hepatic ischemia reperfusion injury through feedback activation of NF-kappaB. J Hepatol. 2014;60:306–12.CrossRefPubMedGoogle Scholar
  26. 26.
    Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431:461–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Greten FR, Karin M. The IKK/NF-kappaB activation pathway-a target for prevention and treatment of cancer. Cancer Lett. 2004;206:193–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Myant KB, Cammareri P, McGhee EJ, Ridgway RA, Huels DJ, Cordero JB, et al. ROS production and NF-kappaB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell Stem Cell. 2013;12:761–73.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Oltulu YM, Coskunpinar E, Ozkan G, Aynaci E, Yildiz P, Isbir T, et al. Investigation of NF-kappaB1 and NF-kappaBIA gene polymorphism in non-small cell lung cancer. Biomed Res Int. 2014;2014:530381.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Li P, Gu J, Yang X, Cai H, Tao J, Lu Q, et al. Functional promoter -94 ins/del ATTG polymorphism in NFKB1 gene is associated with bladder cancer risk in a Chinese population. PLoS One. 2013;8:e71604.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    DiDonato JA, Mercurio F, Karin M. NF-kappaB and the link between inflammation and cancer. Immunol Rev. 2012;246:379–400.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Donghua Xu
    • 1
    • 2
    • 3
  • Xiaochen Wang
    • 2
    • 3
  • Shushan Yan
    • 2
    • 3
  • Yin Yin
    • 2
    • 3
  • Jiajie Hou
    • 2
    • 3
  • Xuehao Wang
    • 2
    • 3
  • Beicheng Sun
    • 2
    • 3
    • 4
  1. 1.Department of Rheumatology, the First Affiliated HospitalNanjing Medical UniversityNanjingChina
  2. 2.Liver Transplantation Center, the First Affiliated HospitalNanjing Medical UniversityNanjingChina
  3. 3.State Key Laboratory of Reproductive MedicineNanjing Medical UniversityNanjingChina
  4. 4.Key Laboratory of Living Donor Liver TransplantationMinistry of HealthNanjingChina

Personalised recommendations