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Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition

Oncogene volume 35, pages 1271–1282 (2016)Cite this article

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Abstract

Epithelial-to-mesenchymal transition (EMT), marked by the dissolution of cell–cell junctions, loss of cell polarity and increased cell motility, is one of the essential steps for prostate cancer metastasis. However, the underlying mechanism has not been fully explored. We report in this study that Shp2 is upregulated in prostate cancers and is associated with a poor disease outcome, namely tumor metastasis and shortened patient survival. Overexpression of wild-type Shp2 or an oncogenic Shp2 mutant leads to increased prostate cancer cell proliferation, colony and sphere formation, and in vivo tumor formation. Opposite effects are seen in Shp2-knockdown cells. Moreover, Shp2 promotes in vitro migration and in vivo metastasis of prostatic tumor cells. Mechanistically, Shp2 interacts with PAR3 (partitioning-defective 3) via its Src homology-2 domain. Ectopic expression of Shp2 attenuates the phosphorylation of PAR3 and the formation of the PAR3/PAR6/atypical protein kinase C polarity protein complex, resulting in disrupted cell polarity, dysregulated cell–cell junctions and increased EMT. These findings provide a novel mechanism by which oncogenic signal-transduction molecules regulate cell polarity and induction of EMT.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.

    PubMed  Google Scholar 

  2. Shen MM, Abate-Shen C . Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev 2010; 24: 1967–2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Valastyan S, Weinberg RA . Tumor metastasis: molecular insights and evolving paradigms. Cell 2011; 147: 275–292.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Tam WL, Weinberg RA . The epigenetics of epithelial–mesenchymal plasticity in cancer. Nat Med 2013; 19: 1438–1449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Li P, Yang R, Gao WQ . Contributions of epithelial–mesenchymal transition and cancer stem cells to the development of castration resistance of prostate cancer. Mol cancer 2014; 13: 55.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Etienne-Manneville S . Polarity proteins in migration and invasion. Oncogene 2008; 27: 6970–6980.

    Article  CAS  PubMed  Google Scholar 

  7. Goldstein B, Macara IG . The PAR proteins: fundamental players in animal cell polarization. Dev Cell 2007; 13: 609–622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Macara IG . Parsing the polarity code. Nat Rev Mol Cell Biol 2004; 5: 220–231.

    Article  CAS  PubMed  Google Scholar 

  9. Suzuki A, Ohno S . The PAR-aPKC system: lessons in polarity. J Cell Sci 2006; 119: 979–987.

    Article  CAS  PubMed  Google Scholar 

  10. Aranda V, Haire T, Nolan ME, Calarco JP, Rosenberg AZ, Fawcett JP et al. Par6-aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control. Nat Cell Biol 2006; 8: 1235–1245.

    Article  CAS  PubMed  Google Scholar 

  11. Wang Y, Du D, Fang L, Yang G, Zhang C, Zeng R et al. Tyrosine phosphorylated Par3 regulates epithelial tight junction assembly promoted by EGFR signaling. EMBO J 2006; 25: 5058–5070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Saadat I, Higashi H, Obuse C, Umeda M, Murata-Kamiya N, Saito Y et al. Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature 2007; 447: 330–333.

    Article  CAS  PubMed  Google Scholar 

  13. Zhu HH, Feng GS . The dynamic interplay between a PTK (Kit) and a PTP (Shp2) in hematopoietic stem and progenitor cells. Cell Cycle 2011; 10: 2241–2242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhu HH, Ji K, Alderson N, He Z, Li S, Liu W et al. Kit-Shp2-Kit signaling acts to maintain a functional hematopoietic stem and progenitor cell pool. Blood 2011; 117: 5350–5361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tartaglia M, Gelb BD . Noonan syndrome and related disorders: genetics and pathogenesis. Annu Rev Genomics Hum Genet 2005; 6: 45–68.

    Article  CAS  PubMed  Google Scholar 

  16. Chan RJ, Feng GS . PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. Blood 2007; 109: 862–867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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: 629–639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sausgruber N, Coissieux MM, Britschgi A, Wyckoff J, Aceto N, Leroy C et al. Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases. Oncogene 2014; 34: 2272–2278.

    Article  PubMed  Google Scholar 

  19. Schneeberger VE, Luetteke N, Ren Y, Berns H, Chen L, Foroutan P et al. SHP2E76K mutant promotes lung tumorigenesis in transgenic mice. Carcinogenesis 2014; 35: 1717–1725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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: 529–537.

    Article  CAS  PubMed  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: 8816–8820.

    Article  CAS  PubMed  Google Scholar 

  22. Wang FM, Liu HQ, Liu SR, Tang SP, Yang L, Feng GS . SHP-2 promoting migration and metastasis of MCF-7 with loss of E-cadherin, dephosphorylation of FAK and secretion of MMP-9 induced by IL-1beta in vivo and in vitro. Breast Cancer Res Treat 2005; 89: 5–14.

    Article  CAS  PubMed  Google Scholar 

  23. 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: 651–664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yang X, Dutta U, Shaw LM . SHP2 mediates the localized activation of Fyn downstream of the alpha6beta4 integrin to promote carcinoma invasion. Mol Cell Biol 2010; 30: 5306–5317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhou XD, Agazie YM . Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells. Cell Death Differ 2008; 15: 988–996.

    Article  CAS  PubMed  Google Scholar 

  26. Yang Z, Xue B, Umitsu M, Ikura M, Muthuswamy SK, Neel BG . The signaling adaptor GAB1 regulates cell polarity by acting as a PAR protein scaffold. Mol Cell 2012; 47: 469–483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bard-Chapeau EA, Yuan J, Droin N, Long S, Zhang EE, Nguyen TV et al. Concerted functions of Gab1 and Shp2 in liver regeneration and hepatoprotection. Mol Cell Biol 2006; 26: 4664–4674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wohrle FU, Daly RJ, Brummer T . Function, regulation and pathological roles of the Gab/DOS docking proteins. Cell Commun Signal 2009; 7: 22.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Feng GS, Hui CC, Pawson T . SH2-containing phosphotyrosine phosphatase as a target of protein-tyrosine kinases. Science 1993; 259: 1607–1611.

    Article  CAS  PubMed  Google Scholar 

  30. Mali RS, Ma P, Zeng LF, Martin H, Ramdas B, He Y et al. Role of SHP2 phosphatase in KIT-induced transformation: identification of SHP2 as a druggable target in diseases involving oncogenic KIT. Blood 2012; 120: 2669–2678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kodama A, Matozaki T, Fukuhara A, Kikyo M, Ichihashi M, Takai Y . Involvement of an SHP-2-Rho small G protein pathway in hepatocyte growth factor/scatter factor-induced cell scattering. Mol Biol Cell 2000; 11: 2565–2575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Martin-Belmonte F, Perez-Moreno M . Epithelial cell polarity, stem cells and cancer. Nat Rev Cancer 2012; 12: 23–38.

    Article  CAS  Google Scholar 

  33. Knoblich JA . Mechanisms of asymmetric stem cell division. Cell 2008; 132: 583–597.

    Article  CAS  PubMed  Google Scholar 

  34. Huang L, Muthuswamy SK . Polarity protein alterations in carcinoma: a focus on emerging roles for polarity regulators. Curr Opin Genet Dev 2010; 20: 41–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang J, Zhu HH, Chu M, Liu Y, Zhang C, Liu G et al. Symmetrical and asymmetrical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages. Nat Commun 2014; 5: 4758.

    Article  CAS  PubMed  Google Scholar 

  36. McCaffrey LM, Montalbano J, Mihai C, Macara IG . Loss of the Par3 polarity protein promotes breast tumorigenesis and metastasis. Cancer Cell 2012; 22: 601–614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Iden S, van Riel WE, Schafer R, Song JY, Hirose T, Ohno S et al. Tumor type-dependent function of the par3 polarity protein in skin tumorigenesis. Cancer Cell 2012; 22: 389–403.

    Article  CAS  PubMed  Google Scholar 

  38. Karantanos T, Corn PG, Thompson TC . Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene 2013; 32: 5501–5511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Takahashi A, Tsutsumi R, Kikuchi I, Obuse C, Saito Y, Seidi A et al. SHP2 tyrosine phosphatase converts parafibromin/Cdc73 from a tumor suppressor to an oncogenic driver. Mol Cell 2011; 43: 45–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lu Y, Xiong Y, Huo Y, Han J, Yang X, Zhang R et al. Grb-2-associated binder 1 (Gab1) regulates postnatal ischemic and VEGF-induced angiogenesis through the protein kinase A-endothelial NOS pathway. Proc Natl Acad Sci USA 2011; 108: 2957–2962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhou Z, Ji Z, Wang Y, Li J, Cao H, Zhu HH et al. TRIM59 is up-regulated in gastric tumors, promoting ubiquitination and degradation of p53. Gastroenterology 2014; 147: 1043–1054.

    Article  CAS  PubMed  Google Scholar 

  42. Liu P, Ramachandran S, Ali Seyed M, Scharer CD, Laycock N, Dalton WB et al. Sex-determining region Y box 4 is a transforming oncogene in human prostate cancer cells. Cancer Res 2006; 66: 4011–4019.

    Article  CAS  PubMed  Google Scholar 

  43. Yu YP, Landsittel D, Jing L, Nelson J, Ren B, Liu L et al. Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J Clin Oncol 2004; 22: 2790–2799.

    Article  CAS  PubMed  Google Scholar 

  44. Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012; 487: 239–243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The study is supported by funds to W-Q Gao from the Chinese Ministry of Science and Technology (2012CB966800 and 2013CB945600), the National Natural Science Foundation of China (NSFC, 81130038 and 81372189), the Science and Technology Commission of Shanghai Municipality (Pujiang program), the Shanghai Health Bureau Key Discipline and Specialty Foundation, the Shanghai Education Committee Key Discipline and Specialty Foundation (J50208) and the KC Wong foundation, and by funds to HH Zhu from the NSFC (81270627), the Science and Technology Commission of Shanghai Municipality (Pujiang program 12PJ1406100) and the Shanghai Education Committee (Chenguang program12CG16, 13YZ030 and young investigator program) and Shanghai Institutions of Higher Learning (The Program for Professor of Special Appointment (Young Eastern Scholar)).

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Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

    K Zhang, H Zhao, Z Ji, C Zhang, P Zhou, L Wang, Q Chen, J Wang, H H Zhu & W-Q Gao

  2. Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    P Zhang

  3. School of Life Science and Technology, Shanghai Tech University, Shanghai, China

    Z Chen

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Zhang, K., Zhao, H., Ji, Z. et al. Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition. Oncogene 35, 1271–1282 (2016). https://doi.org/10.1038/onc.2015.184

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