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Down-regulation of Protease-activated Receptor 4 in Lung Adenocarcinoma is Associated with a More Aggressive Phenotype

  • Jiang, Ping (Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences) ;
  • Yu, Guo-Yu (Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences) ;
  • Zhang, Yong (Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences) ;
  • Xiang, Yang (Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences) ;
  • Hua, Hai-Rong (Department of Pathology and Pathophysiology, Kunming Medical University) ;
  • Bian, Li (Department of Pathology, the First Affiliated Hospital of Kunming Medical University) ;
  • Wang, Chun-Yan (University of Chinese Academy of Sciences) ;
  • Lee, Wen-Hui (Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences) ;
  • Zhang, Yun (Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences)
  • Published : 2013.06.30

Abstract

The role of protease-activated receptors (PARs) in lung tumors is controversial. Although PAR4 is preferentially expressed in human lung tissues, its possible significance in lung cancer has not been defined. The studies reported herein used a combination of clinical observations and molecular methods. Surgically resected lung adenocarcinomas and associated adjacent normal lung tissues were collected and BEAS-2B and NCI-H157 cell lines were grown in tissue culture. PAR4 expression was evaluated by RT-PCR, RT-qPCR, Western blotting and immunohistochemistry analysis. The results showed that PAR4 mRNA expression was generally decreased in lung adenocarcinoma tissues as compared with matched noncancerous tissues (67.7%) and was associated with poor differentiation (p=0.017) and metastasis (p=0.04). Western blotting and immunohistochemical analysis also showed that PAR4 protein levels were mostly decreased in lung adenocarcinoma tissues (61.3%), and were also associated with poor differentiation (p=0.035) and clinical stage (p=0.027). Moreover, PAR4 expression was decreased in NCI-H157 cells as compared with BEAS-2B cells. In conclusion, PAR4 expression is significantly decreased in lung adenocarcinoma, and down-regulation of PAR4 is associated with a more clinically aggressive phenotype. PAR4 may acts as a tumor suppressor in lung adenocarcinoma.

Keywords

PAR4;down-regulation;tumor suppressor;lung cancer;adenocarcinoma

References

  1. Ahmad R, Knafo L, Xu J, et al (2000). Thrombin induces apoptosis in human tumor cells. Int J Cancer, 87, 707-15. https://doi.org/10.1002/1097-0215(20000901)87:5<707::AID-IJC13>3.0.CO;2-W
  2. Camerer E, Qazi AA, Duong DN, et al (2004). Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis. Blood, 104, 397-401. https://doi.org/10.1182/blood-2004-02-0434
  3. Darmoul D, Gratio V, Devaud H, et al (2003). Aberrant expression and activation of the thrombin receptor protease-activated receptor-1 induces cell proliferation and motility in human colon cancer cells. Am J Pathol, 162, 1503-13. https://doi.org/10.1016/S0002-9440(10)64283-6
  4. Darmoul D, Marie JC, Devaud H, et al (2001). Initiation of human colon cancer cell proliferation by trypsin acting at proteaseactivated receptor-2. Br J Cancer, 85, 772-9. https://doi.org/10.1054/bjoc.2001.1976
  5. Dorsam RT, Gutkind JS (2007). G-protein-coupled receptors and cancer. Nat Rev Cancer, 7, 79-94. https://doi.org/10.1038/nrc2069
  6. Elste AP, Petersen I (2010). Expression of proteinase-activated receptor 1-4 (PAR 1-4) in human cancer. J Mol Histol, 41, 89-99. https://doi.org/10.1007/s10735-010-9274-6
  7. Fujiwara M, Jin E, Ghazizadeh MK, awanami O (2005). Activation of PAR4 induces a distinct actin fiber formation via p38 MAPK in human lung endothelial cells. J Histochem Cytochem, 53, 1121-9. https://doi.org/10.1369/jhc.4A6592.2005
  8. Ghio P, Cappia S, Selvaggi G, et al (2006). Prognostic role of protease-activated receptors 1 and 4 in resected stage IB non-small-cell lung cancer. Clin Lung Cancer, 7, 395-400. https://doi.org/10.3816/CLC.2006.n.023
  9. Gratio V, Walker F, Lehy T, et al (2009). Aberrant expression of proteinase-activated receptor 4 promotes colon cancer cell proliferation through a persistent signaling that involves Src and ErbB-2 kinase. Int J Cancer, 124, 1517-25. https://doi.org/10.1002/ijc.24070
  10. Guo H, Ingolia NT, Weissman JS, Bartel DP (2010). Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature, 466, 835-40. https://doi.org/10.1038/nature09267
  11. Huang YQ, Li JJ, Karpatkin S (2000). Thrombin inhibits tumor cell growth in association with up-regulation of p21(waf/cip1) and caspases via a p53-independent, STAT-1-dependent pathway. J Biol Chem, 275, 6462-8. https://doi.org/10.1074/jbc.275.9.6462
  12. Italiano JE, Jr., Richardson JL, Patel-Hett S, et al (2008). Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood, 111, 1227-33.
  13. Kahn M, Ishii K, Kuo WL, et al (1996). Conserved structure and adjacent location of the thrombin receptor and proteaseactivated receptor 2 genes define a protease-activated receptor gene cluster. Mol Med, 2, 349-57.
  14. Kaufmann R, Rahn S, Pollrich K, et al (2007). Thrombin-mediated hepatocellular carcinoma cell migration: cooperative action via proteinase-activated receptors 1 and 4. J Cell Physiol, 211, 699-707. https://doi.org/10.1002/jcp.21027
  15. Kononen J, Bubendorf L, Kallioniemi A, et al (1998). Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med, 4, 844-7. https://doi.org/10.1038/nm0798-844
  16. Lan RS, Stewart G AHenry PJ (2002). Role of protease-activated receptors in airway function: a target for therapeutic intervention? Pharmacol Ther, 95, 239-57. https://doi.org/10.1016/S0163-7258(02)00237-1
  17. Liu SB, He YY, Zhang Y, et al (2008). A novel non-lens betagammacrystallin and trefoil factor complex from amphibian skin and its functional implications. PLoS One, 3, e1770. https://doi.org/10.1371/journal.pone.0001770
  18. Ma L, Perini R, McKnight W, et al (2005). Proteinase-activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets. Proc Natl Acad Sci U S A, 102, 216-20. https://doi.org/10.1073/pnas.0406682102
  19. Moss SF, Lee JW, Sabo E, et al (2008). Decreased expression of gastrokine 1 and the trefoil factor interacting protein TFIZ1/GKN2 in gastric cancer: influence of tumor histology and relationship to prognosis. Clin Cancer Res, 14, 4161-7. https://doi.org/10.1158/1078-0432.CCR-07-4381
  20. Nelken NA, Soifer SJ, O’Keefe J, et al (1992). Thrombin receptor expression in normal and atherosclerotic human arteries. J Clin Invest, 90, 1614-21. https://doi.org/10.1172/JCI116031
  21. Peters T, Henry PJ (2009). Protease-activated receptors and prostaglandins in inflammatory lung disease. Br J Pharmacol, 158, 1017-33. https://doi.org/10.1111/j.1476-5381.2009.00449.x
  22. Ramachandran R, Hollenberg MD (2008). Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more. Br J Pharmacol, 153, S263-82. https://doi.org/10.1038/sj.bjp.0707486
  23. Rudroff C, Seibold S, Kaufmann R, et al (2002). Expression of the thrombin receptor PAR-1 correlates with tumour cell differentiation of pancreatic adenocarcinoma in vitro. Clin Exp Metastasis, 19, 181-9. https://doi.org/10.1023/A:1014598904644
  24. Rullier A, Senant N, Kisiel W, et al (2006). Expression of proteaseactivated receptors and tissue factor in human liver. Virchows Arch, 448, 46-51. https://doi.org/10.1007/s00428-005-0078-0
  25. Saifeddine M, Al-Ani B, Sandhu S, et al (2001). Contractile actions of proteinase-activated receptor-derived polypeptides in guinea-pig gastric and lung parenchymal strips: evidence for distinct receptor systems. Br J Pharmacol, 132, 556-66. https://doi.org/10.1038/sj.bjp.0703839
  26. Siegel R, Naishadham D, Jemal A (2012). Cancer statistics, 2012. CA Cancer J Clin, 62, 10-29. https://doi.org/10.3322/caac.20138
  27. Sokolova E, Reiser G (2007). A novel therapeutic target in various lung diseases: airway proteases and protease-activated receptors. Pharmacol Ther, 115, 70-83. https://doi.org/10.1016/j.pharmthera.2007.04.002
  28. Toh CK (2009). The changing epidemiology of lung cancer. Methods Mol Biol, 472, 397-411. https://doi.org/10.1007/978-1-60327-492-0_19
  29. Tomankova T, Petrek M, Kriegova E (2010). Involvement of microRNAs in physiological and pathological processes in the lung. Respir Res, 11, 159. https://doi.org/10.1186/1465-9921-11-159
  30. Trejo J (2003). Protease-activated receptors: new concepts in regulation of G protein-coupled receptor signaling and trafficking. J Pharmacol Exp Ther, 307, 437-42. https://doi.org/10.1124/jpet.103.052100
  31. Vergnolle N, Wallace JL, Bunnett NW, Hollenberg MD (2001). Protease-activated receptors in inflammation, neuronal signaling and pain. Trends Pharmacol Sci, 22, 146-52. https://doi.org/10.1016/S0165-6147(00)01634-5
  32. Xu WF, Andersen H, Whitmore TE, et al (1998). Cloning and characterization of human protease-activated receptor 4. Proc Natl Acad Sci U S A, 95, 6642-6. https://doi.org/10.1073/pnas.95.12.6642
  33. Zhang H, Cai B (2003). The impact of tobacco on lung health in China. Respirology, 8, 17-21. https://doi.org/10.1046/j.1440-1843.2003.00433.x
  34. Zhang Y, Yu G, Jiang P, et al (2011). Decreased expression of protease-activated receptor 4 in human gastric cancer. Int J Biochem Cell Biol, 43, 1277-83. https://doi.org/10.1016/j.biocel.2011.05.008

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