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Expression and prognosis value of SHP2 in patients with pancreatic ductal adenocarcinoma

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Tumor Biology

Abstract

SHP2 is an src homology (SH) 2 domain-containing protein tyrosine phosphatase (PTP). SHP2 implicitly contributes to tumorigenesis, but the role of SHP2 in pancreatic ductal adenocarcinoma is still unknown. The purpose of this study was to evaluate the prognostic significance and associated expression of SHP2 in pancreatic ductal adenocarcinoma (PDAC) patients. We used immunohistochemistry to assess the protein expression levels of SHP2 in 79 PDAC specimens. The correlations between SHP2 expression and various clinicopathological features were evaluated by Pearson’s chi-square (χ 2) test, Fisher’s exact test, and Spearman’s rank. Univariate and multivariate Cox regression analyses were used to identify correlations between the immunohistochemical data for SHP2 expression and the clinicopathologic characteristics in PDAC. Kaplan-Meier survival analysis was used to demonstrate the relation between overall survival and the expression of SHP2. Immunohistochemistry revealed significantly higher rates of high SHP2 expression in PDAC tissues (55.7 %) versus adjacent non-cancer tissues (10.1 %) (P < 0.05). Expression of SHP2 was only significantly correlated with histological differentiation (P = 0.033) and vital status (P = 0.025). Patients with high SHP2 expression had shorter overall survival times compared to those with low SHP2 expression (P = 0.000). Multivariate Cox regression analysis revealed that SHP2 overexpression was an independent prognostic factor in PDAC (P = 0.012). Our study demonstrated for the first time that higher expression of SHP2 might be involved in the progression of pancreatic ductal adenocarcinoma, suggesting that SHP2 may be a potential prognostic marker and target for therapy.

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References

  1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.

    Article  PubMed  Google Scholar 

  2. Gong Z, Holly EA, Bracci PM. Survival in population-based pancreatic cancer patients: San Francisco Bay area, 1995–1999. Am J Epidemiol. 2011;174:1373–81.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378:607–20.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Katz MH, Wang H, Fleming JB, Sun CC, Hwang RF, Wolff RA, et al. Long-term survival after multidisciplinary management of resected pancreatic adenocarcinoma. Ann Surg Oncol. 2009;16:836–47.

    Article  PubMed  PubMed Central  Google Scholar 

  5. He C, Jiang H, Geng S, Sheng H, Shen X, Zhang X, et al. Expression and prognostic value of c-Myc and Fas (CD95/APO1) in patients with pancreatic cancer. Int J Clin Exp Pathol. 2014;7:742–50.

    PubMed  PubMed Central  Google Scholar 

  6. Qu CK. Role of the SHP-2 tyrosine phosphatase in cytokine-induced signaling and cellular response. Biochim Biophys Acta. 2002;1592:297–301.

    Article  CAS  PubMed  Google Scholar 

  7. Freeman RJ, Plutzky J, Neel BG. Identification of a human src homology 2-containing protein-tyrosine-phosphatase: a putative homolog of Drosophila corkscrew. Proc Natl Acad Sci U S A. 1992;89:11239–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ahmad S, Banville D, Zhao Z, Fischer EH, Shen SH. A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains. Proc Natl Acad Sci U S A. 1993;90:2197–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Vogel W, Lammers R, Huang J, Ullrich A. Activation of a phosphotyrosine phosphatase by tyrosine phosphorylation. Science. 1993;259:1611–4.

    Article  CAS  PubMed  Google Scholar 

  10. Feng GS, Hui CC, Pawson T. SH2-containing phosphotyrosine phosphatase as a target of protein-tyrosine kinases. Science. 1993;259:1607–11.

    Article  CAS  PubMed  Google Scholar 

  11. Koch CA, Anderson D, Moran MF, Ellis C, Pawson T. SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science. 1991;252:668–74.

    Article  CAS  PubMed  Google Scholar 

  12. Motiwala T, Jacob ST. Role of protein tyrosine phosphatases in cancer. Prog Nucleic Acid Res Mol Biol. 2006;81:297–329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hartman ZR, Schaller MD, Agazie YM. The tyrosine phosphatase SHP2 regulates focal adhesion kinase to promote EGF-induced lamellipodia persistence and cell migration. Mol Cancer Res. 2013;11:651–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kandadi MR, Stratton MS, Ren J. The role of Src homology 2 containing protein tyrosine phosphatase 2 in vascular smooth muscle cell migration and proliferation. Acta Pharmacol Sin. 2010;31:1277–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Noguchi T, Matozaki T, Horita K, Fujioka Y, Kasuga M. Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in insulin-stimulated Ras activation. Mol Cell Biol. 1994;14:6674–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Feng GS. Shp2-mediated molecular signaling in control of embryonic stem cell self-renewal and differentiation. Cell Res. 2007;17:37–41.

    Article  CAS  PubMed  Google Scholar 

  17. Selimoglu-Buet D, Gallais I, Denis N, Guillouf C, Moreau-Gachelin F. Oncogenic kit triggers Shp2/Erk1/2 pathway to down-regulate the pro-apoptotic protein Bim and to promote apoptosis resistance in leukemic cells. PLoS One. 2012;7:e49052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dong S, Li FQ, Zhang Q, Lv KZ, Yang HL, Gao Y, et al. Expression and clinical significance of SHP2 in gastric cancer. J Int Med Res. 2012;40:2083–9.

    Article  CAS  PubMed  Google Scholar 

  19. Chan RJ, Feng GS. PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. Blood. 2007;109:862–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ren Y, Chen Z, Chen L, Fang B, Win-Piazza H, Haura E, et al. Critical role of Shp2 in tumor growth involving regulation of c-Myc. Genes Cancer. 2010;1:994–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bentires-Alj M, Paez JG, David FS, Keilhack H, Halmos B, Naoki K, et al. Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 2004;64:8816–20.

    Article  CAS  PubMed  Google Scholar 

  22. Hu Z, Fang H, Wang X, Chen D, Chen Z, Wang S. Overexpression of SHP2 tyrosine phosphatase promotes the tumorigenesis of breast carcinoma. Oncol Rep. 2014;32:205–12.

    CAS  PubMed  Google Scholar 

  23. Wang HC, Chiang WF, Huang HH, Shen YY, Chiang HC. Src-homology 2 domain-containing tyrosine phosphatase 2 promotes oral cancer invasion and metastasis. BMC Cancer. 2014;14:442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. He HY, Zheng J, Li Y, Heng WJ, Fang WG. SHP2 and MKP5 in P2Y purinergic receptor-mediated prostate cancer invasion. Zhonghua Bing Li Xue Za Zhi. 2005;34:288–92.

    PubMed  Google Scholar 

  25. Zhan X, Dong H, Sun C, Liu L, Wang D, Wei Z. Expression and clinical significance of SHP2 in the tumor tissues of smokers with lung cancer. Zhongguo Fei Ai Za Zhi. 2010;13:877–81.

    PubMed  Google Scholar 

  26. Leibowitz MS, Srivastava RM, Andrade FP, Egloff AM, Wang L, Seethala RR, et al. SHP2 is overexpressed and inhibits pSTAT1-mediated APM component expression, T-cell attracting chemokine secretion, and CTL recognition in head and neck cancer cells. Clin Cancer Res. 2013;19:798–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bard-Chapeau EA, Li S, Ding J, Zhang SS, Zhu HH, Princen F, et al. Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis. Cancer Cell. 2011;19:629–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nabinger SC, Chan RJ. Shp2 function in hematopoietic stem cell biology and leukemogenesis. Curr Opin Hematol. 2012;19:273–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Grosskopf S, Eckert C, Arkona C, Radetzki S, Bohm K, Heinemann U, et al. Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in vitro and in vivo. ChemMedChem. 2015;10:815–26.

    Article  CAS  PubMed  Google Scholar 

  30. Tempero MA, Arnoletti JP, Behrman S, Ben-Josef E, Benson AR, Berlin JD, et al. Pancreatic adenocarcinoma. J Natl Compr Cancer Netw. 2010;8:972–1017.

    CAS  Google Scholar 

  31. Zhang LJ, Wang KB, Liu LS, Chen LZ, Peng BG, Liang LJ, et al. Overexpression of GOLPH3 is associated with poor prognosis and clinical progression in pancreatic ductal adenocarcinoma. BMC Cancer. 2014;14:571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Aceto N, Sausgruber N, Brinkhaus H, Gaidatzis D, Martiny-Baron G, Mazzarol G, et al. Tyrosine phosphatase SHP2 promotes breast cancer progression and maintains tumor-initiating cells via activation of key transcription factors and a positive feedback signaling loop. Nat Med. 2012;18:529–37.

    Article  CAS  PubMed  Google Scholar 

  33. 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 

  34. Muenst S, Obermann EC, Gao F, Oertli D, Viehl CT, Weber WP, et al. Src homology phosphotyrosyl phosphatase-2 expression is an independent negative prognostic factor in human breast cancer. Histopathology. 2013;63:74–82.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mohi MG, Neel BG. The role of Shp2 (PTPN11) in cancer. Curr Opin Genet Dev. 2007;17:23–30.

    Article  CAS  PubMed  Google Scholar 

  36. Gomes EG, Connelly SF, Summy JM. Targeting the yin and the yang: combined inhibition of the tyrosine kinase c-Src and the tyrosine phosphatase SHP-2 disrupts pancreatic cancer signaling and biology in vitro and tumor formation in vivo. Pancreas. 2013;42:795–806.

    Article  CAS  PubMed  Google Scholar 

  37. Grossmann KS, Rosario M, Birchmeier C, Birchmeier W. The tyrosine phosphatase Shp2 in development and cancer. Adv Cancer Res. 2010;106:53–89.

    Article  CAS  PubMed  Google Scholar 

  38. Neel BG, Gu H, Pao L. The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci. 2003;28:284–93.

    Article  CAS  PubMed  Google Scholar 

  39. Rosario M, Birchmeier W. How to make tubes: signaling by the Met receptor tyrosine kinase. Trends Cell Biol. 2003;13:328–35.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Xiong Chen.

Ethics declarations

This study was approved by the Ethics Review Committee of the Fuzhou General Hospital of Nanjing Military Command, and each patient signed an informed consent form before enrollment into the study.

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Funding

This work was funded by grants from the National Natural Science Foundation of China (No. 81302067 and No. 81302164).

Additional information

Jiawei Zheng and Shanshan Huang contributed equally to this work.

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Zheng, J., Huang, S., Huang, Y. et al. Expression and prognosis value of SHP2 in patients with pancreatic ductal adenocarcinoma. Tumor Biol. 37, 7853–7859 (2016). https://doi.org/10.1007/s13277-015-4675-5

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  • DOI: https://doi.org/10.1007/s13277-015-4675-5

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