Protease-activated receptor-1 (PAR-1): A promising molecular target for cancer

Oncotarget

Volumn 8, Issue 63, 2017, Pages 107334-107345

  Liu, Xuan ^a,b   Yu, Jiahui ^b   Song, Shangjin ^b   Yue, Xiaoqiang ^b   Li, Qi ^a  

^a SHANGHAI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE   (China)

^b SECOND MILITARY MEDICAL UNIVERSITY   (China)

Author keywords

Cancer; Carcinogenesis; Invasion; Metastasis; PAR 1

Indexed keywords

PROTEINASE ACTIVATED RECEPTOR 1; VORAPAXAR;

ARTICLE; BLEEDING; BREAST CANCER; CANCER INHIBITION; COLORECTAL CANCER; DRUG TARGETING; ENZYME ACTIVATION; ENZYME REGULATION; HUMAN; LUNG CANCER; MELANOMA; METASTASIS; OVARY CANCER; PANCREAS CANCER; PROSTATE CANCER; PROTEIN FUNCTION; PROTEIN TARGETING; RENAL CELL CARCINOMA; SIGNAL TRANSDUCTION; STOMACH CANCER; TUMOR INVASION;

EID: 85036604799     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.21015     Document Type: Article

References (116)

1. Rasmussen UB, Vouret-Craviari V, Jallat S, Schlesinger Y, Pagès G, Pavirani A, Lecocq JP, Pouysségur J, Van Obberghen-Schilling E. cDNA cloning and expression of a hamster alpha-thrombin receptor coupled to Ca2+ mobilization. FEBS Lett. 1991; 288:123-8. https://doi.org/10.1016/0014-5793(91)81017-3
2. Vu TK, Hung DT, Wheaton VI, Coughlin SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell. 1991; 64:1057-68. https://doi.org/10.1016/0092-8674(91)90261-V
3. Austin KM, Covic L, Kuliopulos A. Matrix metalloproteases and PAR1 activation. Blood. 2013; 121:431-9. https://doi.org/10.1182/blood-2012-09-355958
4. Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost. 2005; 3:1800-14. https://doi.org/10.1111/j.1538-7836.2005.01377.x
5. Nieman MT. PARtitioning protease signaling. Blood. 2015; 125:1853-5. https://doi.org/10.1182/blood-2015-01-623835
6. Lin H, Liu AP, Smith TH, Trejo J. Cofactoring and dimerization of proteinase-activated receptors. Pharmacol Rev. 2013; 65:1198-213. https://doi.org/10.1124/pr.111.004747
7. Aisiku O, Peters CG, De Ceunynck K, Ghosh CC, Dilks JR, Fustolo-Gunnink SF, Huang M, Dockendorff C, Parikh SM, Flaumenhaft R. Parmodulins inhibit thrombus formation without inducing endothelial injury caused by vorapaxar. Blood. 2015; 125:1976-85. https://doi.org/10.1182/blood-2014-09-599910
8. Arora P, Ricks TK, Trejo J. Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer. J Cell Sci. 2007; 120:921-8. https://doi.org/10.1242/jcs.03409
9. White MJ, Gomer RH. Trypsin, Tryptase, and Thrombin Polarize Macrophages towards a Pro-Fibrotic M2a Phenotype. PLoS One. 2015; 10:e0138748. https://doi.org/10.1371/journal.pone.0138748
10. Yang E, Boire A, Agarwal A, Nguyen N, O'Callaghan K, Tu P, Kuliopulos A, Covic L. Blockade of PAR1 signaling with cell-penetrating pepducins inhibits Akt survival pathways in breast cancer cells and suppresses tumor survival and metastasis. Cancer Res. 2009; 69:6223-31. https://doi.org/10.1158/0008-5472.CAN-09-0187
11. Villares GJ, Zigler M, Wang H, Melnikova VO, Wu H, Friedman R, Leslie MC, Vivas-Mejia PE, Lopez-Berestein G, Sood AK, Bar-Eli M. Targeting melanoma growth and metastasis with systemic delivery of liposome-incorporated protease-activated receptor-1 small interfering RNA. Cancer Res. 2008; 68:9078-86. https://doi.org/10.1158/0008-5472.CAN-08-2397
12. Tatour M, Shapira M, Axelman E, Ghanem S, Keren-Politansky A, Bonstein L, Brenner B, Nadir Y. Thrombin is a selective inducer of heparanase release from platelets and granulocytes via protease-activated receptor-1. Thromb Haemost. 2017; 117:1391-401. https://doi.org/10.1160/TH16-10-0766
13. Baker NC, Lipinski MJ, Lhermusier T, Waksman R. Overview of the 2014 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee meeting about vorapaxar. Circulation. 2014; 130:1287-94. https://doi.org/10.1161/CIRCULATIONAHA.114.011471
14. Wang A. Review of vorapaxar for the prevention of atherothrombotic events. Expert Opin Pharmacother. 2015; 16:2509-22. https://doi.org/10.1517/14656566.2015.1099629
15. Klonaris C, Patelis N, Drebes A, Matheiken S, Liakakos T. Antiplatelet Treatment in Peripheral Arterial Disease: The Role of Novel Antiplatelet Agents. Curr Pharm Des. 2016; 22:4610-6. https://doi.org/10.2174/1381612822666160607065109
16. Niespialowska-Steuden M, Collins P, Costopoulos C, Gorog DA. NOAC in acute coronary syndrome and AF? Cardiovasc Hematol Disord Drug Targets. 2014; 14:154-64. https://doi.org/10.2174/1871529X14666140701100338
17. Cunningham M, McIntosh K, Bushell T, Sloan G, Plevin R. Proteinase-activated receptors (PARs) as targets for antiplatelet therapy. Biochem Soc Trans. 2016; 44:606-12. https://doi.org/10.1042/BST20150282
18. Moschonas IC, Goudevenos JA, Tselepis AD. Protease-activated receptor-1 antagonists in long-term antiplatelet therapy. Current state of evidence and future perspectives. Int J Cardiol. 2015; 185:9-18. https://doi.org/10.1016/j.ijcard.2015.03.049
19. Smokers under 50 have eightfold increased risk of heart attack. Nurs Stand. 2017; 31:16. https://doi.org/10.7748/ns.31.19.16.s18
20. Chanakira A, Westmark PR, Ong IM, Sheehan JP. Tissue factor-factor VIIa complex triggers protease activated receptor 2-dependent growth factor release and migration in ovarian cancer. Gynecol Oncol. 2017; 145:167-75. https://doi.org/10.1016/j.ygyno.2017.01.022
21. Wiviott SD, Flather MD, O'Donoghue ML, Goto S, Fitzgerald DJ, Cura F, Aylward P, Guetta V, Dudek D, Contant CF, Angiolillo DJ, Bhatt DL, Investigators L-C. Randomized trial of atopaxar in the treatment of patients with coronary artery disease: the lessons from antagonizing the cellular effect of Thrombin-Coronary Artery Disease Trial. Circulation. 2011; 123:1854-63. https://doi.org/10.1161/CIRCULATIONAHA.110.001404
22. Goto S, Ogawa H, Takeuchi M, Flather MD, Bhatt DL, Investigators JL. Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease. Eur Heart J. 2010; 31:2601-13. https://doi.org/10.1093/eurheartj/ehq320
23. O'Donoghue ML, Bhatt DL, Wiviott SD, Goodman SG, Fitzgerald DJ, Angiolillo DJ, Goto S, Montalescot G, Zeymer U, Aylward PE, Guetta V, Dudek D, Ziecina R, et al. Safety and tolerability of atopaxar in the treatment of patients with acute coronary syndromes: the lessons from antagonizing the cellular effects of Thrombin-Acute Coronary Syndromes Trial. Circulation. 2011; 123:1843-53. https://doi.org/10.1161/CIRCULATIONAHA.110.000786
24. Yuan SM, Nie WC, He F, Jia ZW, Gao XD. Kin2, the Budding Yeast Ortholog of Animal MARK/PAR-1 Kinases, Localizes to the Sites of Polarized Growth and May Regulate Septin Organization and the Cell Wall. PLoS One. 2016; 11:e0153992. https://doi.org/10.1371/journal.pone.0153992
25. Trivedi V, Boire A, Tchernychev B, Kaneider NC, Leger AJ, O'Callaghan K, Covic L, Kuliopulos A. Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site. Cell. 2009; 137:332-43. https://doi.org/10.1016/j.cell.2009.02.018
26. Malaquin N, Vercamer C, Bouali F, Martien S, Deruy E, Wernert N, Chwastyniak M, Pinet F, Abbadie C, Pourtier A. Senescent fibroblasts enhance early skin carcinogenic events via a paracrine MMP-PAR-1 axis. PLoS One. 2013; 8:e63607. https://doi.org/10.1371/journal.pone.0063607
27. Albrektsen T, Sorensen BB, Hjorto GM, Fleckner J, Rao LV, Petersen LC. Transcriptional program induced by factor VIIa-tissue factor, PAR1 and PAR2 in MDA-MB-231 cells. J Thromb Haemost. 2007; 5:1588-97. https://doi.org/10.1111/j.1538-7836.2007.02603.x
28. Hudak R, Vincze J, Csernoch L, Beke Debreceni I, Olah T, Erdodi F, Clemetson KJ, Kappelmayer J. The Phosphatase Inhibitor Calyculin-A Impairs Clot Retraction, Platelet Activation, and Thrombin Generation. Biomed Res Int. 2017; 2017:9795271. https://doi.org/10.1155/2017/9795271
29. Grimsey N, Lin H, Trejo J. Endosomal signaling by protease-activated receptors. Methods Enzymol. 2014; 535:389-401. https://doi.org/10.1016/B978-0-12-397925-4.00022-5
30. Soh UJ, Dores MR, Chen B, Trejo J. Signal transduction by protease-activated receptors. Br J Pharmacol. 2010; 160:191-203. https://doi.org/10.1111/j.1476-5381.2010.00705.x
31. Gullapalli A, Wolfe BL, Griffin CT, Magnuson T, Trejo J. An essential role for SNX1 in lysosomal sorting of protease-activated receptor-1: evidence for retromer-, Hrs-, and Tsg101-independent functions of sorting nexins. Mol Biol Cell. 2006; 17:1228-38. https://doi.org/10.1091/mbc.E05-09-0899
32. Nierodzik ML, Karpatkin S. Thrombin induces tumor growth, metastasis, and angiogenesis: Evidence for a thrombin-regulated dormant tumor phenotype. Cancer Cell. 2006; 10:355-62. https://doi.org/10.1016/j.ccr.2006.10.002
33. Saleiban A, Faxalv L, Claesson K, Jonsson JI, Osman A. miR-20b regulates expression of proteinase-activated receptor-1 (PAR-1) thrombin receptor in melanoma cells. Pigment Cell Melanoma Res. 2014; 27:431-41. https://doi.org/10.1111/pcmr.12217
34. Zigler M, Kamiya T, Brantley EC, Villares GJ, Bar-Eli M. PAR-1 and thrombin: the ties that bind the microenvironment to melanoma metastasis. Cancer Res. 2011; 71:6561-6. https://doi.org/10.1158/0008-5472.CAN-11-1432
35. Villares GJ, Zigler M, Bar-Eli M. The emerging role of the thrombin receptor (PAR-1) in melanoma metastasis a possible therapeutic target. Oncotarget. 2011; 2:8-17. https://doi.org/10.18632/oncotarget.211
36. Tatour M, Shapira M, Axelman E, Ghanem S, Keren-Politansky A, Bonstein L, Brenner B, Nadir Y. Thrombin is a selective inducer of heparanase release from platelets and granulocytes via protease-activated receptor-1. Thromb Haemost. 2017; 117:1391-401. https://doi.org/10.1160/TH16-10-0766
37. Wang Q, Liu Q, Wang T, Yang H, Han Z, Zhang P. Endothelial cell protein C receptor promotes MGC803 gastric cancer cells proliferation and migration by activating ERK1/2. Med Oncol. 2015; 32:162. https://doi.org/10.1007/s12032-015-0614-y
38. Even-Ram S, Uziely B, Cohen P, Grisaru-Granovsky S, Maoz M, Ginzburg Y, Reich R, Vlodavsky I, Bar-Shavit R. Thrombin receptor overexpression in malignant and physiological invasion processes. Nat Med. 1998; 4:909-14. https://doi.org/10.1038/nm0898-909
39. Won JH, Zhang Y, Ji B, Logsdon CD, Yule DI. Phenotypic changes in mouse pancreatic stellate cell Ca2+ signaling events following activation in culture and in a disease model of pancreatitis. Mol Biol Cell. 2011; 22:421-36. https://doi.org/10.1091/mbc.E10-10-0807
40. Zigler M, Kamiya T, Brantley EC, Villares GJ, Bar-Eli M. PAR-1 and thrombin: the ties that bind the microenvironment to melanoma metastasis. Cancer Res. 2011; 71:6561-6. https://doi.org/10.1158/0008-5472.CAN-11-1432
41. Kim SJ, Shin JY, Lee KD, Bae YK, Choi IJ, Park SH, Chun KH. Galectin-3 facilitates cell motility in gastric cancer by up-regulating protease-activated receptor-1 (PAR-1) and matrix metalloproteinase-1 (MMP-1). PLoS One. 2011; 6:e25103. https://doi.org/10.1371/journal.pone.0025103
42. Chang LH, Chen CH, Huang DY, Pai HC, Pan SL, Teng CM. Thrombin induces expression of twist and cell motility via the hypoxia-inducible factor-1alpha translational pathway in colorectal cancer cells. J Cell Physiol. 2011; 226:1060-8. https://doi.org/10.1002/jcp.22428
43. Sedda S, Marafini I, Caruso R, Pallone F, Monteleone G. Proteinase activated-receptors-associated signaling in the control of gastric cancer. World J Gastroenterol. 2014; 20:11977-84. https://doi.org/10.3748/wjg.v20.i34.11977
44. Fujimoto D, Hirono Y, Goi T, Katayama K, Yamaguchi A. Prognostic value of protease-activated receptor-1 (PAR-1) and matrix metalloproteinase-1 (MMP-1) in gastric cancer. Anticancer Res. 2008; 28:847-54
45. Moon JY, Franchi F, Rollini F, Angiolillo DJ. Role for Thrombin Receptor Antagonism With Vorapaxar in Secondary Prevention of Atherothrombotic Events: From Bench to Bedside. J Cardiovasc Pharmacol Ther. 2017: 1074248417708617. https://doi.org/10.1177/1074248417708617
46. Whetstone WD, Walker B, Trivedi A, Lee S, Noble-Haeusslein LJ, Hsu JC. Protease-Activated Receptor-1 Supports Locomotor Recovery by Biased Agonist Activated Protein C after Contusive Spinal Cord Injury. PLoS One. 2017; 12:e0170512. https://doi.org/10.1371/journal.pone.0170512
47. Otsuki T, Fujimoto D, Hirono Y, Goi T, Yamaguchi A. Thrombin conducts epithelialmesenchymal transition via proteaseactivated receptor1 in human gastric cancer. Int J Oncol. 2014; 45:2287-94. https://doi.org/10.3892/ijo.2014.2651
48. Borensztajn KS, Bijlsma MF, Groot AP, Bruggemann LW, Versteeg HH, Reitsma PH, Peppelenbosch MP, Spek CA. Coagulation factor Xa drives tumor cells into apoptosis through BH3-only protein Bim up-regulation. Exp Cell Res. 2007; 313:2622-33. https://doi.org/10.1016/j.yexcr.2007.04.014
49. Mahajan VB, Pai KS, Lau A, Cunningham DD. Creatine kinase, an ATP-generating enzyme, is required for thrombin receptor signaling to the cytoskeleton. Proc Natl Acad Sci U S A. 2000; 97:12062-7. https://doi.org/10.1073/pnas.97.22.12062
50. Even-Ram SC, Maoz M, Pokroy E, Reich R, Katz BZ, Gutwein P, Altevogt P, Bar-Shavit R. Tumor cell invasion is promoted by activation of protease activated receptor-1 in cooperation with the alpha vbeta 5 integrin. J Biol Chem. 2001; 276:10952-62. https://doi.org/10.1074/jbc.M007027200
51. Bai SY, Xu N, Chen C, Song YL, Hu J, Bai CX. Integrin alphavbeta5 as a biomarker for the assessment of non-small cell lung cancer metastasis and overall survival. Clin Respir J. 2015; 9:457-67. https://doi.org/10.1111/crj.12163
52. Trikha M, Timar J, Zacharek A, Nemeth JA, Cai Y, Dome B, Somlai B, Raso E, Ladanyi A, Honn KV. Role for beta3 integrins in human melanoma growth and survival. Int J Cancer. 2002; 101:156-67. https://doi.org/10.1002/ijc.10521
53. Raso E, Tovari J, Toth K, Paku S, Trikha M, Honn KV, Timar J. Ectopic alphaIIbbeta3 integrin signaling involves 12-lipoxygenase-and PKC-mediated serine phosphorylation events in melanoma cells. Thromb Haemost. 2001; 85:1037-42
54. Amador MA, Cavalcante GC, Santos NP, Gusmao L, Guerreiro JF, Ribeiro-dos-Santos A, Santos S. Distribution of allelic and genotypic frequencies of IL1A, IL4, NFKB1 and PAR1 variants in Native American, African, European and Brazilian populations. BMC Res Notes. 2016; 9:101. https://doi.org/10.1186/s13104-016-1906-9
55. Massi D, Naldini A, Ardinghi C, Carraro F, Franchi A, Paglierani M, Tarantini F, Ketabchi S, Cirino G, Hollenberg MD, Geppetti P, Santucci M. Expression of protease-activated receptors 1 and 2 in melanocytic nevi and malignant melanoma. Hum Pathol. 2005; 36:676-85. https://doi.org/10.1016/j.humpath.2005.04.008
56. Maeda S, Nakajima K, Tohyama Y, Kohsaka S. Characteristic response of astrocytes to plasminogen/plasmin to upregulate transforming growth factor beta 3 (TGFbeta3) production/secretion through proteinase-activated receptor-1 (PAR-1) and the downstream phosphatidylinositol 3-kinase (PI3K)-Akt/PKB signaling cascade. Brain Res. 2009; 1305:1-13. https://doi.org/10.1016/j.brainres.2009.09.025
57. Yin YJ, Salah Z, Maoz M, Even Ram SC, Ochayon S, Neufeld G, Katzav S, Bar-Shavit R. Oncogenic transformation induces tumor angiogenesis: a role for PAR1 activation. FASEB J. 2003; 17:163-74. https://doi.org/10.1096/fj.02-0316com
58. Zain J, Huang YQ, Feng X, Nierodzik ML, Li JJ, Karpatkin S. Concentration-dependent dual effect of thrombin on impaired growth/apoptosis or mitogenesis in tumor cells. Blood. 2000; 95:3133-8
59. Liu L, Yan B, Yang Z, Zhang X, Gu Q, Yue X. ncRuPAR inhibits gastric cancer progression by down-regulating protease-activated receptor-1. Tumour Biol. 2014; 35:7821-9. https://doi.org/10.1007/s13277-014-2042-6
60. Xie Q, Bao X, Chen ZH, Xu Y, Keep RF, Muraszko KM, Xi G, Hua Y. Role of Protease-Activated Receptor-1 in Glioma Growth. Acta Neurochir Suppl. 2016; 121:355-60. https://doi.org/10.1007/978-3-319-18497-5_61
61. Huang Z, Miao X, Luan Y, Zhu L, Kong F, Lu Q, Pernow J, Nilsson G, Li N. PAR1-stimulated platelet releasate promotes angiogenic activities of endothelial progenitor cells more potently than PAR4-stimulated platelet releasate. J Thromb Haemost. 2015; 13:465-76. https://doi.org/10.1111/jth.12815
62. Reinhardt C, Bergentall M, Greiner TU, Schaffner F, Ostergren-Lunden G, Petersen LC, Ruf W, Backhed F. Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling. Nature. 2012; 483:627-31. https://doi.org/10.1038/nature10893
63. Morris DR, Ding Y, Ricks TK, Gullapalli A, Wolfe BL, Trejo J. Protease-activated receptor-2 is essential for factor VIIa and Xa-induced signaling, migration, and invasion of breast cancer cells. Cancer Res. 2006; 66:307-14. https://doi.org/10.1158/0008-5472.CAN-05-1735
64. Fujimoto D, Hirono Y, Goi T, Katayama K, Matsukawa S, Yamaguchi A. The activation of Proteinase-Activated Receptor-1 (PAR1) mediates gastric cancer cell proliferation and invasion. BMC Cancer. 2010; 10:443. https://doi.org/10.1186/1471-2407-10-443
65. Uzunoglu FG, Yavari N, Bohn BA, Nentwich MF, Reeh M, Pantel K, Perez D, Tsui TY, Bockhorn M, Mann O, Izbicki JR, Wikman H, Vashist YK. C-X-C motif receptor 2, endostatin and proteinase-activated receptor 1 polymorphisms as prognostic factors in NSCLC. Lung Cancer. 2013; 81:123-9. https://doi.org/10.1016/j.lungcan.2013.03.007
66. Uzunoglu FG, Kolbe J, Wikman H, Gungor C, Bohn BA, Nentwich MF, Reeh M, Konig AM, Bockhorn M, Kutup A, Mann O, Izbicki JR, Vashist YK. VEGFR-2, CXCR-2 and PAR-1 germline polymorphisms as predictors of survival in pancreatic carcinoma. Ann Oncol. 2013; 24:1282-90. https://doi.org/10.1093/annonc/mds634
67. Li SM, Jiang P, Xiang Y, Wang WW, Zhu YC, Feng WY, Li SD, Yu GY. Protease-activated receptor (PAR)1, PAR2 and PAR4 expressions in esophageal squamous cell carcinoma. Dongwuxue Yanjiu. 2014; 35:420-5. https://doi.org/10.13918/j.issn.2095-8137.2014.5.420
68. Liao M, Tong P, Zhao J, Zhang Y, Li Z, Wang J, Feng X, Hu M, Pan Y. Prognostic value of matrix metalloproteinase-1/ proteinase-activated receptor-1 signaling axis in hepatocellular carcinoma. Pathol Oncol Res. 2012; 18:397-403. https://doi.org/10.1007/s12253-011-9458-8
69. Yin YJ, Salah Z, Grisaru-Granovsky S, Cohen I, Even-Ram SC, Maoz M, Uziely B, Peretz T, Bar-Shavit R. Human protease-activated receptor 1 expression in malignant epithelia: a role in invasiveness. Arterioscler Thromb Vasc Biol. 2003; 23:940-4. https://doi.org/10.1161/01.ATV.0000066878.27340.22
70. Vianello F, Sambado L, Goss A, Fabris F, Prandoni P. Dabigatran antagonizes growth, cell-cycle progression, migration, and endothelial tube formation induced by thrombin in breast and glioblastoma cell lines. Cancer Med. 2016; 5:2886-98. https://doi.org/10.1002/cam4.857
71. Jaber M, Maoz M, Kancharla A, Agranovich D, Peretz T, Grisaru-Granovsky S, Uziely B, Bar-Shavit R. Protease-activated-receptor-2 affects protease-activated-receptor-1-driven breast cancer. Cell Mol Life Sci. 2014; 71:2517-33. https://doi.org/10.1007/s00018-013-1498-7
72. Ohshiro K, Bui-Nguyen TM, Divijendra Natha RS, Schwartz AM, Levine P, Kumar R. Thrombin stimulation of inflammatory breast cancer cells leads to aggressiveness via the EGFR-PAR1-Pak1 pathway. Int J Biol Markers. 2012; 27:e305-13. https://doi.org/10.5301/JBM.2012.10437
73. Silini A, Ghilardi C, Ardinghi C, Bernasconi S, Oliva P, Carraro F, Naldini A, Bani MR, Giavazzi R. Protease-activated receptor-1 (PAR-1) promotes the motility of human melanomas and is associated to their metastatic phenotype. Clin Exp Metastasis. 2010; 27:43-53. https://doi.org/10.1007/s10585-009-9301-8
74. Blackburn JS, Liu I, Coon CI, Brinckerhoff CE. A matrix metalloproteinase-1/protease activated receptor-1 signaling axis promotes melanoma invasion and metastasis. Oncogene. 2009; 28:4237-48. https://doi.org/10.1038/onc.2009.272
75. Villares GJ, Zigler M, Bar-Eli M. The emerging role of the thrombin receptor (PAR-1) in melanoma metastasis a possible therapeutic target. Oncotarget. 2011; 2:8-17. https://doi.org/10.18632/oncotarget.211
76. Melnikova VO, Balasubramanian K, Villares GJ, Dobroff AS, Zigler M, Wang H, Petersson F, Price JE, Schroit A, Prieto VG, Hung MC, Bar-Eli M. Crosstalk between protease-activated receptor 1 and platelet-activating factor receptor regulates melanoma cell adhesion molecule (MCAM/MUC18) expression and melanoma metastasis. J Biol Chem. 2009; 284:28845-55. https://doi.org/10.1074/jbc.M109.042150
77. Waitkus MS, Chandrasekharan UM, Willard B, Tee TL, Hsieh JK, Przybycin CG, Rini BI, Dicorleto PE. Signal integration and gene induction by a functionally distinct STAT3 phosphoform. Mol Cell Biol. 2014; 34:1800-11. https://doi.org/10.1128/MCB.00034-14
78. Villares GJ, Zigler M, Wang H, Melnikova VO, Wu H, Friedman R, Leslie MC, Vivas-Mejia PE, Lopez-Berestein G, Sood AK, Bar-Eli M. Targeting melanoma growth and metastasis with systemic delivery of liposome-incorporated protease-activated receptor-1 small interfering RNA. Cancer Res. 2008; 68:9078-86. https://doi.org/10.1158/0008-5472.CAN-08-2397
79. Otsuki T, Fujimoto D, Hirono Y, Goi T, Yamaguchi A. Thrombin conducts epithelialmesenchymal transition via proteaseactivated receptor1 in human gastric cancer. Int J Oncol. 2014; 45:2287-94. https://doi.org/10.3892/ijo.2014.2651
80. Pang L, Li JF, Su L, Zang M, Fan Z, Yu B, Wu X, Li C, Yan M, Zhu ZG, Liu B. ALEX1, a novel tumor suppressor gene, inhibits gastric cancer metastasis via the PAR-1/Rho GTPase signaling pathway. J Gastroenterol. 2017. https://doi.org/10.1007/s00535-017-1329-y
81. Clouston HW, Davenport A, Gregson H, Shaker H, Duff S, Kirwan CC. PO-51-Expression of proteins of the tissue factor thrombin pathway is upregulated in the stroma and epithelium of colorectal cancer. Thromb Res. 2016; 140:S195. https://doi.org/10.1016/S0049-3848(16)30184-0
82. Tas F, Karabulut S, Tastekin D, Duranyildiz D. Clinical significance of serum protease-activated receptor-1 levels in gastric cancer patients. Biomed Rep. 2016; 4:489-92. https://doi.org/10.3892/br.2016.606
83. Adams GN, Rosenfeldt L, Frederick M, Miller W, Waltz D, Kombrinck K, McElhinney KE, Flick MJ, Monia BP, Revenko AS, Palumbo JS. Colon Cancer Growth and Dissemination Relies upon Thrombin, Stromal PAR-1, and Fibrinogen. Cancer Res. 2015; 75:4235-43. https://doi.org/10.1158/0008-5472.CAN-15-0964
84. Yan B, Gu W, Yang Z, Gu Z, Yue X, Gu Q, Liu L. Downregulation of a long noncoding RNA-ncRuPAR contributes to tumor inhibition in colorectal cancer. Tumour Biol. 2014; 35:11329-35. https://doi.org/10.1007/s13277-014-2465-0
85. Jia Y, Zhang S, Miao L, Wang J, Jin Z, Gu B, Duan Z, Zhao Z, Ma S, Zhang W, Li Z. Activation of platelet protease-activated receptor-1 induces epithelial-mesenchymal transition and chemotaxis of colon cancer cell line SW620. Oncol Rep. 2015; 33:2681-8. https://doi.org/10.3892/or.2015.3897
86. Gratio V, Beaufort N, Seiz L, Maier J, Virca GD, Debela M, Grebenchtchikov N, Magdolen V, Darmoul D. Kallikrein-related peptidase 4: a new activator of the aberrantly expressed protease-activated receptor 1 in colon cancer cells. Am J Pathol. 2010; 176:1452-61. https://doi.org/10.2353/ajpath.2010.090523
87. Goerge T, Barg A, Schnaeker EM, Poppelmann B, Shpacovitch V, Rattenholl A, Maaser C, Luger TA, Steinhoff M, Schneider SW. Tumor-derived matrix metalloproteinase-1 targets endothelial proteinase-activated receptor 1 promoting endothelial cell activation. Cancer Res. 2006; 66:7766-74. https://doi.org/10.1158/0008-5472.CAN-05-3897
88. Nguyen QD, De Wever O, Bruyneel E, Hendrix A, Xie WZ, Lombet A, Leibl M, Mareel M, Gieseler F, Bracke M, Gespach C. Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho-Rho kinase axis and tumor microenvironment. Oncogene. 2005; 24:8240-51. https://doi.org/10.1038/sj.onc.1208990
89. Darmoul D, Gratio V, Devaud H, Peiretti F, Laburthe M. Activation of proteinase-activated receptor 1 promotes human colon cancer cell proliferation through epidermal growth factor receptor transactivation. Mol Cancer Res. 2004; 2:514-22
90. Erturk K, Tastekin D, Bilgin E, Tas F, Disci R, Duranyildiz D. Clinical significance of serum protease activated receptor1 levels in patients with lung cancer. Eur Rev Med Pharmacol Sci. 2016; 20:243-9
91. Lin C, Majoor CJ, Roelofs JJ, de Kruif MD, Horlings HM, Borensztajn K, Spek CA. Potential importance of protease activated receptor (PAR)-1 expression in the tumor stroma of non-small-cell lung cancer. BMC Cancer. 2017; 17:113. https://doi.org/10.1186/s12885-017-3081-3
92. Uzunoglu FG, Yavari N, Bohn BA, Nentwich MF, Reeh M, Pantel K, Perez D, Tsui TY, Bockhorn M, Mann O, Izbicki JR, Wikman H, Vashist YK. C-X-C motif receptor 2, endostatin and proteinase-activated receptor 1 polymorphisms as prognostic factors in NSCLC. Lung Cancer. 2013; 81:123-9. https://doi.org/10.1016/j.lungcan.2013.03.007
93. Riedl J, Kaider A, Marosi C, Prager G, Eichelberger B, Koder S, Panzer S, Pabinger I, Ay C. PO-63-Exhausted platelets in cancer patients with high risk of venous thromboembolism and poor prognosis. Thromb Res. 2016; 140 Suppl 1: S199-200. https://doi.org/10.1016/S0049-3848(16)30196-7
94. Wu Z, Zeng Y, Zhong M, Wang B. Targeting A549 lung adenocarcinoma cell growth and invasion with proteaseactivated receptor1 siRNA. Mol Med Rep. 2014; 9:1787-93. https://doi.org/10.3892/mmr.2014.2023
95. Smoktunowicz N, Plate M, Stern AO, D'Antongiovanni V, Robinson E, Chudasama V, Caddick S, Scotton CJ, Jarai G, Chambers RC. TGFbeta upregulates PAR-1 expression and signalling responses in A549 lung adenocarcinoma cells. Oncotarget. 2016; 7:65471-84. https://doi.org/10.18632/oncotarget.11472
96. Castellone MD, Laukkanen MO, Teramoto H, Bellelli R, Ali G, Fontanini G, Santoro M, Gutkind JS. Cross talk between the bombesin neuropeptide receptor and Sonic hedgehog pathways in small cell lung carcinoma. Oncogene. 2015; 34:1679-87. https://doi.org/10.1038/onc.2014.104
97. Queiroz KC, Shi K, Duitman J, Aberson HL, Wilmink JW, van Noesel CJ, Richel DJ, Spek CA. Protease-activated receptor-1 drives pancreatic cancer progression and chemoresistance. Int J Cancer. 2014; 135:2294-304. https://doi.org/10.1002/ijc.28726
98. Uzunoglu FG, Kolbe J, Wikman H, Gungor C, Bohn BA, Nentwich MF, Reeh M, Konig AM, Bockhorn M, Kutup A, Mann O, Izbicki JR, Vashist YK. VEGFR-2, CXCR-2 and PAR-1 germline polymorphisms as predictors of survival in pancreatic carcinoma. Ann Oncol. 2013; 24:1282-90. https://doi.org/10.1093/annonc/mds634
99. Queiroz KC, Shi K, Duitman J, Aberson HL, Wilmink JW, van Noesel CJ, Richel DJ, Spek CA. Protease-activated receptor-1 drives pancreatic cancer progression and chemoresistance. Int J Cancer. 2014; 135:2294-304. https://doi.org/10.1002/ijc.28726
100. Kanemaru M, Maehara N, Iwamura T, Chijiiwa K. Thrombin stimulates integrin beta1-dependent adhesion of human pancreatic cancer cells to vitronectin through protease-activated receptor (PAR)-1. Hepatogastroenterology. 2012; 59:1614-20. https://doi.org/10.5754/hge10036
101. Wang H, Yi T, Zheng Y, He S. Induction of monocyte chemoattractant protein-1 release from A549 cells by agonists of protease-activated receptor-1 and-2. Eur J Cell Biol. 2007; 86:233-42. https://doi.org/10.1016/j.ejcb.2006.12.003
102. Zhang X, Wang W, True LD, Vessella RL, Takayama TK. Protease-activated receptor-1 is upregulated in reactive stroma of primary prostate cancer and bone metastasis. Prostate. 2009; 69:727-36. https://doi.org/10.1002/pros.20920
103. Wang J, Liu D, Zhou W, Wang M, Xia W, Tang Q. Prognostic value of matrix metalloprotease-1/protease-activated receptor-1 axis in patients with prostate cancer. Med Oncol. 2014; 31:968. https://doi.org/10.1007/s12032-014-0968-6
104. Gao L, Smith RS, Chen LM, Chai KX, Chao L, Chao J. Tissue kallikrein promotes prostate cancer cell migration and invasion via a protease-activated receptor-1-dependent signaling pathway. Biol Chem. 2010; 391:803-12. https://doi.org/10.1515/BC.2010.084
105. Wang W, Mize GJ, Zhang X, Takayama TK. Kallikrein-related peptidase-4 initiates tumor-stroma interactions in prostate cancer through protease-activated receptor-1. Int J Cancer. 2010; 126:599-610. https://doi.org/10.1002/ijc.24904
106. Yang R, Xu Y, Li P, Zhang X, Wang J, Gu D, Wang Y. Combined upregulation of matrix metalloproteinase-1 and proteinase-activated receptor-1 predicts unfavorable prognosis in human nasopharyngeal carcinoma. Onco Targets Ther. 2013; 6:1139-46. https://doi.org/10.2147/OTT.S50389
107. Zhu Q, Luo J, Wang T, Ren J, Hu K, Wu G. The activation of protease-activated receptor 1 mediates proliferation and invasion of nasopharyngeal carcinoma cells. Oncol Rep. 2012; 28:255-61. https://doi.org/10.3892/or.2012.1802
108. Fazzini A, D'Antongiovanni V, Giusti L, Da Valle Y, Ciregia F, Piano I, Caputo A, D'Ursi AM, Gargini C, Lucacchini A, Mazzoni MR. Altered protease-activated receptor-1 expression and signaling in a malignant pleural mesothelioma cell line, NCI-H28, with homozygous deletion of the beta-catenin gene. PLoS One. 2014; 9:e111550. https://doi.org/10.1371/journal.pone.0111550
109. Goyama S, Shrestha M, Schibler J, Rosenfeldt L, Miller W, O'Brien E, Mizukawa B, Kitamura T, Palumbo JS, Mulloy JC. Protease-activated receptor-1 inhibits proliferation but enhances leukemia stem cell activity in acute myeloid leukemia. Oncogene. 2017; 36:2589-98. https://doi.org/10.1038/onc.2016.416
110. Li SM, Jiang P, Xiang Y, Wang WW, Zhu YC, Feng WY, Li SD, Yu GY. Protease-activated receptor (PAR)1, PAR2 and PAR4 expressions in esophageal squamous cell carcinoma. Dongwuxue Yanjiu. 2014; 35:420-5. https://doi.org/10.13918/j.issn.2095-8137.2014.5.420
111. Kuhn SA, Martin M, Brodhun M, Kratzsch T, Hanisch UK, Haberl H. Overexpression of protease-activated receptor type 1 (PAR-1) in glioblastoma multiforme WHO IV cells and blood vessels revealed by NCAM-assisted glioblastoma border labeling. Neurol Res. 2014; 36:709-21. https://doi.org/10.1179/1743132813Y.0000000303
112. Krenzlin H, Lorenz V, Alessandri B. The involvement of thrombin in the pathogenesis of glioblastoma. J Neurosci Res. 2017; 95:2080-5. https://doi.org/10.1002/jnr.24049
113. Xie Q, Bao X, Chen ZH, Xu Y, Keep RF, Muraszko KM, Xi G, Hua Y. Role of Protease-Activated Receptor-1 in Glioma Growth. Acta Neurochir Suppl. 2016; 121:355-60. https://doi.org/10.1007/978-3-319-18497-5_61
114. Auvergne R, Wu C, Connell A, Au S, Cornwell A, Osipovitch M, Benraiss A, Dangelmajer S, Guerrero-Cazares H, Quinones-Hinojosa A, Goldman SA. PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo. Oncogene. 2016; 35:3817-28. https://doi.org/10.1038/onc.2015.452
115. Mussbach F, Henklein P, Westermann M, Settmacher U, Bohmer FD, Kaufmann R. Proteinase-activated receptor 1-and 4-promoted migration of Hep3B hepatocellular carcinoma cells depends on ROS formation and RTK transactivation. J Cancer Res Clin Oncol. 2015; 141:813-25. https://doi.org/10.1007/s00432-014-1863-4
116. Martin F, Long JC, O'Toole SA, O'Leary JJ, Abu Saadeh F, Gleeson N, Norris LA. PO-14-Tumour expression of coagulation proteases of the aPC pathway-a role in the pathogenesis of gynaecological cancers? Thromb Res. 2016; 140:S181. https://doi.org/10.1016/S0049-3848(16)30147-5