Skip to main content

Advertisement

SpringerLink
Log in

Tumour-suppressive role of PTPN13 in hepatocellular carcinoma and its clinical significance

  • Original Article
  • Published:
Tumor Biology

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality and carries a dismal prognosis. The present study aimed to identify the tumour-suppressive role and clinical implications of PTPN13 in HCC progression. We tested the effects of PTPN13 expression in proliferation, invasion, epithelial–mesenchymal transition and associated pathways in HCC cell lines in vitro. Furthermore, its clinical relevance was evaluated in a tissue microarray analysis of samples from 282 HCC patients. Various HCC cell lines expressed relatively low PTPN13 protein levels in vitro. PTPN13 overexpression significantly inhibited the progression of HCC cells, possibly by inhibiting epithelial–mesenchymal transition through inactivation of the EGFR/ERK signalling pathway. Tissue microarray analysis revealed that high PTPN13 expression was correlated with a favourable prognosis in postoperative HCC patients. This study demonstrated the tumour suppressor, PTPN13, as an alternative therapeutic target for HCC.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA: Cancer J Clin. 2015;65(2):87–108.

  2. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365:1118–27.

    Article  CAS  PubMed  Google Scholar 

  3. Maluccio M, Covey A. Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA: Cancer J Clin. 2012;62:394–9.

    Google Scholar 

  4. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141:1117–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Julien SG, Dube N, Hardy S, Tremblay ML. Inside the human cancer tyrosine phosphatome. Nat Rev Cancer. 2011;11:35–49.

    Article  CAS  PubMed  Google Scholar 

  6. Gao Q, Zhao YJ, Wang XY, et al. Activating mutations in PTPN3 promote cholangiocarcinoma cell proliferation and migration and are associated with tumor recurrence in patients. Gastroenterology. 2014;146:1397–407.

    Article  CAS  PubMed  Google Scholar 

  7. Chan G, Kalaitzidis D, Neel BG. The tyrosine phosphatase Shp2 (PTPN11) in cancer. Cancer Metastasis Rev. 2008;27:179–92.

    Article  CAS  PubMed  Google Scholar 

  8. Zbuk KM, Eng C. Cancer phenomics: RET and PTEN as illustrative models. Nat Rev Cancer. 2007;7:35–45.

    Article  CAS  PubMed  Google Scholar 

  9. Yeh SH, Wu DC, Tsai CY, et al. Genetic characterization of Fas-associated phosphatase-1 as a putative tumor suppressor gene on chromosome 4q21.3 in hepatocellular carcinoma. Clin Cancer Res. 2006;12:1097–108.

    Article  CAS  PubMed  Google Scholar 

  10. Wang Z, Shen D, Parsons DW, et al. Mutational analysis of the tyrosine phosphatome in colorectal cancers. Sci N Y. 2004;304:1164–6.

    Article  CAS  Google Scholar 

  11. Zhu JH, Chen R, Yi W, et al. Protein tyrosine phosphatase PTPN13 negatively regulates Her2/ErbB2 malignant signaling. Oncogene. 2008;27:2525–31.

    Article  CAS  PubMed  Google Scholar 

  12. Sotelo NS, Schepens JT, Valiente M, et al. PTEN-PDZ domain interactions: binding of PTEN to PDZ domains of PTPN13. Methods. 2015;77–78:147–56.

    Article  PubMed  Google Scholar 

  13. Freiss G, Chalbos D. PTPN13/PTPL1: an important regulator of tumor aggressiveness. Anti Cancer Agents Med Chem. 2011;11:78–88.

    Article  CAS  Google Scholar 

  14. Sun HC, Zhang W, Qin LX, et al. Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma. J Hepatol. 2007;47:684–90.

    Article  CAS  PubMed  Google Scholar 

  15. Gao Q, Wang XY, Qiu SJ, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res: Off J Am Assoc Cancer Res. 2009;15:971–9.

    Article  CAS  Google Scholar 

  16. Zhou SL, Dai Z, Zhou ZJ, et al. Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatol Baltimo, Md. 2012;56:2242–54.

    Article  CAS  Google Scholar 

  17. Wang J, Ren J, Wu B, et al. Activation of Rab8 guanine nucleotide exchange factor Rabin8 by ERK1/2 in response to EGF signaling. Proc Natl Acad Sci U S A. 2015;112:148–53.

    Article  CAS  PubMed  Google Scholar 

  18. Hunter T. Tyrosine phosphorylation: thirty years and counting. Curr Opin Cell Biol. 2009;21:140–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Abaan OD, Toretsky JA. PTPL1: a large phosphatase with a split personality. Cancer Metastasis Rev. 2008;27:205–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Erdmann KS. The protein tyrosine phosphatase PTP-basophil/basophil-like. Eur J Biochem. 2003;270:4789–98.

    Article  CAS  PubMed  Google Scholar 

  21. Ying J, Li H, Cui Y, et al. Epigenetic disruption of two proapoptotic genes MAPK10/JNK3 and PTPN13/FAP-1 in multiple lymphomas and carcinomas through hypermethylation of a common bidirectional promoter. Leukemia. 2006;20:1173–5.

    Article  CAS  PubMed  Google Scholar 

  22. Lucci MA, Orlandi R, Triulzi T, et al. Expression profile of tyrosine phosphatases in HER2 breast cancer cells and tumors. Cell Oncol. 2010;32:361–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Wieckowski E, Atarashi Y, Stanson J, et al. FAP-1-mediated activation of NF-kappaB induces resistance of head and neck cancer to Fas-induced apoptosis. J Cell Biochem. 2007;100:16–28.

    Article  CAS  PubMed  Google Scholar 

  24. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119:1420–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Castilla C, Chinchon D, Medina R, et al. PTPL1 and PKCdelta contribute to proapoptotic signalling in prostate cancer cells. Cell Death Dis. 2013;4:e576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Castilla C, Flores ML, Conde JM, et al. Downregulation of protein tyrosine phosphatase PTPL1 alters cell cycle and upregulates invasion-related genes in prostate cancer cells. Clin Exp Metastasis. 2012;29:349–58.

    Article  CAS  PubMed  Google Scholar 

  27. Scrima M, De Marco C, De Vita F, et al. The nonreceptor-type tyrosine phosphatase PTPN13 is a tumor suppressor gene in non-small cell lung cancer. Am J Pathol. 2012;180:1202–14.

    Article  CAS  PubMed  Google Scholar 

  28. Glondu-Lassis M, Dromard M, Lacroix-Triki M, et al. PTPL1/PTPN13 regulates breast cancer cell aggressiveness through direct inactivation of Src kinase. Cancer Res. 2010;70:5116–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Revillion F, Puech C, Rabenoelina F, et al. Expression of the putative tumor suppressor gene PTPN13/PTPL1 is an independent prognostic marker for overall survival in breast cancer. Int J Cancer. 2009;124:638–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dromard M, Bompard G, Glondu-Lassis M, et al. The putative tumor suppressor gene PTPN13/PTPL1 induces apoptosis through insulin receptor substrate-1 dephosphorylation. Cancer Res. 2007;67:6806–13.

    Article  CAS  PubMed  Google Scholar 

  31. Kawano S, Ikeda W, Kishimoto M, et al. Silencing of ErbB3/ErbB2 signaling by immunoglobulin-like Necl-2. J Biol Chem. 2009;284:23793–805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schickel R, Park SM, Murmann AE, Peter ME. miR-200c regulates induction of apoptosis through CD95 by targeting FAP-1. Mol Cell. 2010;38:908–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gloire G, Charlier E, Piette J. Regulation of CD95/APO-1/Fas-induced apoptosis by protein phosphatases. Biochem Pharmacol. 2008;76:1451–8.

    Article  CAS  PubMed  Google Scholar 

  34. Winterhoff BJ, Arlt A, Duttmann A, et al. Characterisation of FAP-1 expression and CD95 mediated apoptosis in the A818-6 pancreatic adenocarcinoma differentiation system. Differentiation. 2012;83:148–57.

    Article  CAS  PubMed  Google Scholar 

  35. Cuppen E, Nagata S, Wieringa B, Hendriks W. No evidence for involvement of mouse protein-tyrosine phosphatase-BAS-like Fas-associated phosphatase-1 in Fas-mediated apoptosis. J Biol Chem. 1997;272:30215–20.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No. 81502502 and 81472672) and the Yangfan Project for Young Scientists of Shanghai (Grant No. 15YF1402200).

Author information

Authors and Affiliations

  1. Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 180 Fenglin Road, Shanghai, 200032, People’s Republic of China

    Hao Zhan, Chubin Luo, Qiman Sun, Aiwu Ke, Chao Sun, Jinwu Hu, Zhiqiang Hu, Bo Hu, Kai Zhu, Jia Fan, Jian Zhou & Xiaowu Huang

  2. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China

    Jiahao Jiang

  3. Shanghai Key Laboratory of Organ Transplantation, Shanghai, People’s Republic of China

    Qiman Sun, Jia Fan, Jian Zhou & Xiaowu Huang

Authors
  1. Hao Zhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiahao Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chubin Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qiman Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aiwu Ke
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chao Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jinwu Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhiqiang Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bo Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kai Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jia Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jian Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Xiaowu Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaowu Huang.

Ethics declarations

This study was conducted in accordance with the ethical principles of research and was approved by the Zhongshan Hospital Ethics Committee. Informed consent was obtained from each patient following institutional review board protocols.

Conflicts of interest

None

Additional information

Hao Zhan, Jiahao Jiang and Chubin Luo share co-first authorship.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhan, H., Jiang, J., Luo, C. et al. Tumour-suppressive role of PTPN13 in hepatocellular carcinoma and its clinical significance. Tumor Biol. 37, 9691–9698 (2016). https://doi.org/10.1007/s13277-016-4843-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-4843-2

Keywords

Search

Navigation