Plasminogen activation system in oral cancer: Relevance in prognosis and therapy (Review)

Wyganowska-Świątkowska,Marzena; Jankun,Jerzy

doi:10.3892/ijo.2015.3021

Plasminogen activation system in oral cancer: Relevance in prognosis and therapy (Review)

Authors:
- Marzena Wyganowska-Świątkowska
- Jerzy Jankun
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Affiliations: Department of Conservative Dentistry and Periodontology, Poznan University of Medical Sciences, Poznań 60-820, Poland, Urology Research Centre, Department of Urology, College of Medicine, University of Toledo, Toledo, OH 43614, USA
Published online on: May 22, 2015 https://doi.org/10.3892/ijo.2015.3021
Pages: 16-24

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Abstract

Research on carcinogenesis and progress in cancer treatment have reduced mortality of cancer patients. Mortality rates decreased by 1.5% per year from 2001 through 2010 for most types of cancer in men and women. However, oral cancer is still a significant global health problem since incidence and mortality rates are increasing. Oral cavity cancer is ranked the 8th in men and the 14th in women based on data collected between 2006 and 2010 by the National Institute of Health. Furthermore, an increasing incidence of head and neck neoplasms, particularly the tongue cancer among young adults has been reported recently. It is most likely due to increasing human papillomavirus (HPV) infection or the early start of tobacco and alcohol consumption. Treatment of oral cancer patients is mainly surgical and often leads to esthetic and functional deformities, with severe impact on the quality of life. Thus, novel form of treatments and selection of patients with high and low risk of mortality is of high priority for clinical studies. The expression of proteolytic enzymes in tumor and stromal tissues has been shown to have prognostic significance in many human cancers and inhibiting proteolysis can reduce tumor growth in many in vivo and in vitro models. Plasmin, with its activators and inhibitors are of great importance in many human malignances and collectively are called plasminogen activation system (PAS). In this comprehensive review we examine expression, possible prognostic markers and importance for therapy of the PAS members in oral cancer. Literature review suggests that overexpression of urokinase and its receptor are markers of poor outcome, thus, their inhibition can be explored in oral cancer therapy. Role of plasminogen activator inhibitor (PAI-1) is complex and depends on its concentration. Overexpression of PAI-1 favors angiogenesis, metastasis and poor prognosis, although when applied in very high concentrations it inhibits angiogenesis and tumor growth, the phenomenon is described as the PAI-1 paradox.

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1	Edwards BK, Noone AM, Mariotto AB, Simard EP, Boscoe FP, Henley SJ, Jemal A, Cho H, Anderson RN, Kohler BA, et al: Annual Report to the Nation on the status of cancer, 1975–2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer. Cancer. 120:1290–1314. 2014. View Article : Google Scholar :
2	Nemoto RP, Victorino AA, Pessoa GB, da Cunha LL, da Silva JA, Kanda JL and Matos LL: Oral cancer preventive campaigns: are we reaching the real target? Braz J Otorhinolaryngol. 81:44–49. 2015. View Article : Google Scholar
3	Toporcov TN, Znaor A, Zhang ZF, Yu GP, Winn DM, Wei Q, Vilensky M, Vaughan T, Thomson P, Talamini R, et al: Risk factors for head and neck cancer in young adults: A pooled analysis in the INHANCE consortium. Int J Epidemiol. 44:169–185. 2015. View Article : Google Scholar : PubMed/NCBI
4	Walsh T, Liu JL, Brocklehurst P, Glenny AM, Lingen M, Kerr AR, Ogden G, Warnakulasuriya S and Scully C: Clinical assessment to screen for the detection of oral cavity cancer and potentially malignant disorders in apparently healthy adults. Cochrane Database Syst Rev. 11:CD0101732013.PubMed/NCBI
5	Chorostowska-Wynimko J, Swiercz R, Skrzypczak-Jankun E, Wojtowicz A, Selman SH and Jankun J: A novel form of the plasminogen activator inhibitor created by cysteine mutations extends its half-life: Relevance to cancer and angiogenesis. Mol Cancer Ther. 2:19–28. 2003. View Article : Google Scholar : PubMed/NCBI
6	Jankun J and Skrzypczak-Jankun E: Yin and yang of the plasminogen activator inhibitor. Pol Arch Med Wewn. 119:410–417. 2009.PubMed/NCBI
7	Lein M, Jung K, Ortel B, Stephan C, Rothaug W, Juchem R, Johannsen M, Deger S, Schnorr D, Loening S, et al: The new synthetic matrix metalloproteinase inhibitor (Roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model. Oncogene. 21:2089–2096. 2002. View Article : Google Scholar : PubMed/NCBI
8	Al-Horani RA: Serpin regulation of fibrinolytic system: Implications for therapeutic applications in cardiovascular diseases. Cardiovasc Hematol Agents Med Chem. 12:91–125. 2014. View Article : Google Scholar : PubMed/NCBI
9	Iishi H, Tatsuta M, Baba M, Yano H, Uehara H and Nakaizumi A: Suppression by amiloride of bombesin-enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxy-methane. Int J Cancer. 63:716–719. 1995. View Article : Google Scholar : PubMed/NCBI
10	Wyganowska-Świątkowska M, Surdacka A, Skrzypczak-Jankun E and Jankun J: The plasminogen activation system in periodontal tissue (Review). Int J Mol Med. 33:763–768. 2014.
11	Jankun J and Skrzypczak-Jankun E: Plasminogen activator inhibitor with very long half-life (VLHL PAI-1) can reduce bleeding in PAI-1-deficient patients. Cardiovasc Hematol Disord Drug Targets. 13:144–150. 2013.PubMed/NCBI
12	Fortenberry YM: Plasminogen activator inhibitor-1 inhibitors: a patent review (2006-present). Expert Opin Ther Pat. 23:801–815. 2013. View Article : Google Scholar : PubMed/NCBI
13	Ghosh AK and Vaughan DE: PAI-1 in tissue fibrosis. J Cell Physiol. 227:493–507. 2012. View Article : Google Scholar
14	Lindberg P, Larsson A and Nielsen BS: Expression of plasminogen activator inhibitor-1, urokinase receptor and laminin gamma-2 chain is an early coordinated event in incipient oral squamous cell carcinoma. Int J Cancer. 118:2948–2956. 2006. View Article : Google Scholar : PubMed/NCBI
15	Stewart CE and Sayers I: Urokinase receptor orchestrates the plasminogen system in airway epithelial cell function. Lung. 191:215–225. 2013. View Article : Google Scholar : PubMed/NCBI
16	Tang L and Han X: The urokinase plasminogen activator system in breast cancer invasion and metastasis. Biomed Pharmacother. 67:179–182. 2013. View Article : Google Scholar
17	Gershtein ES and Kushlinskii NE: Clinical prospects of tumor-associated proteases and their tissue inhibitors investigation in oncologic patient. Vestn Ross Akad Med Nauk. 16–27. 2013.(In Russian).
18	Weng CJ, Lin CW, Chung TT, Tsai CM, Chen MK and Yang SF: Impact of uPA system gene polymorphisms on the susceptibility of environmental factors to carcinogenesis and the development of clinicopathology of oral cancer. Ann Surg Oncol. 18:805–812. 2011. View Article : Google Scholar
19	Duong HS, Le AD, Zhang Q and Messadi DV: A novel 3-dimensional culture system as an in vitro model for studying oral cancer cell invasion. Int J Exp Pathol. 86:365–374. 2005. View Article : Google Scholar : PubMed/NCBI
20	Yoshizawa K, Nozaki S, Kitahara H, Kato K, Noguchi N, Kawashiri S and Yamamoto E: Expression of urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor and maspin in oral squamous cell carcinoma: Association with mode of invasion and clinicopathological factors. Oncol Rep. 26:1555–1560. 2011.PubMed/NCBI
21	Lescaille G, Menashi S, Cavelier-Balloy B, Khayati F, Quemener C, Podgorniak MP, Naïmi B, Calvo F, Lebbe C and Mourah S: EMMPRIN/CD147 up-regulates urokinase-type plasminogen activator: Implications in oral tumor progression. BMC Cancer. 12:1152012. View Article : Google Scholar : PubMed/NCBI
22	Zhang Z, Pan J, Li L, Wang Z, Xiao W and Li N: Survey of risk factors contributed to lymphatic metastasis in patients with oral tongue cancer by immunohistochemistry. J Oral Pathol Med. 40:127–134. 2011. View Article : Google Scholar
23	Curino A, Patel V, Nielsen BS, Iskander AJ, Ensley JF, Yoo GH, Holsinger FC, Myers JN, El-Nagaar A, Kellman RM, et al: Detection of plasminogen activators in oral cancer by laser capture microdissection combined with zymography. Oral Oncol. 40:1026–1032. 2004. View Article : Google Scholar : PubMed/NCBI
24	Gaarenstroom KN, Kenter GG, Bonfrer JM, Korse CM, Van de Vijver MJ, Fleuren GJ and Trimbos JB: Can initial serum cyfra 21-1, SCC antigen, and TPA levels in squamous cell cervical cancer predict lymph node metastases or prognosis? Gynecol Oncol. 77:164–170. 2000. View Article : Google Scholar : PubMed/NCBI
25	Jankun J, Maher VM and McCormick JJ: Malignant transformation of human fibroblasts correlates with increased activity of receptor-bound plasminogen activator. Cancer Res. 51:1221–1226. 1991.PubMed/NCBI
26	Jankun J, Merrick HW and Goldblatt PJ: Expression and localization of elements of the plasminogen activation system in benign breast disease and breast cancers. J Cell Biochem. 53:135–144. 1993. View Article : Google Scholar : PubMed/NCBI
27	Zubac DP, Wentzel-Larsen T, Seidal T and Bostad L: Type 1 plasminogen activator inhibitor (PAI-1) in clear cell renal cell carcinoma (CCRCC) and its impact on angiogenesis, progression and patient survival after radical nephrectomy. BMC Urol. 10:202010. View Article : Google Scholar : PubMed/NCBI
28	Harbeck N, Schmitt M, Paepke S, Allgayer H and Kates RE: Tumor-associated proteolytic factors uPA and PAI-1: Critical appraisal of their clinical relevance in breast cancer and their integration into decision-support algorithms. Crit Rev Clin Lab Sci. 44:179–201. 2007. View Article : Google Scholar : PubMed/NCBI
29	Schrohl AS, Holten-Andersen MN, Peters HA, Look MP, Meijervan Gelder ME, Klijn JG, Brünner N and Foekens JA: Tumor tissue levels of tissue inhibitor of metalloproteinase-1 as a prognostic marker in primary breast cancer. Clin Cancer Res. 10:2289–2298. 2004. View Article : Google Scholar : PubMed/NCBI
30	Borstnar S, Vrhovec I, Svetic B and Cufer T: Prognostic value of the urokinase-type plasminogen activator, and its inhibitors and receptor in breast cancer patients. Clin Breast Cancer. 3:138–146. 2002. View Article : Google Scholar : PubMed/NCBI
31	Grøndahl-Hansen J, Christensen IJ, Briand P, Pappot H, Mouridsen HT, Blichert-Toft M, Danø K and Brünner N: Plasminogen activator inhibitor type 1 in cytosolic tumor extracts predicts prognosis in low-risk breast cancer patients. Clin Cancer Res. 3:233–239. 1997.PubMed/NCBI
32	Duggan C, Maguire T, McDermott E, O’Higgins N, Fennelly JJ and Duffy MJ: Urokinase plasminogen activator and urokinase plasminogen activator receptor in breast cancer. Int J Cancer. 61:597–600. 1995. View Article : Google Scholar : PubMed/NCBI
33	McMahon B and Kwaan HC: The plasminogen activator system and cancer. Pathophysiol Haemost Thromb. 36:184–194. 2008. View Article : Google Scholar
34	McMahon GA, Petitclerc E, Stefansson S, Smith E, Wong MK, Westrick RJ, Ginsburg D, Brooks PC and Lawrence DA: Plasminogen activator inhibitor-1 regulates tumor growth and angiogenesis. J Biol Chem. 276:33964–33968. 2001. View Article : Google Scholar : PubMed/NCBI
35	Swiercz R, Keck RW, Skrzypczak-Jankun E, Selman SH and Jankun J: Recombinant PAI-1 inhibits angiogenesis and reduces size of LNCaP prostate cancer xenografts in SCID mice. Oncol Rep. 8:463–470. 2001.PubMed/NCBI
36	Kwaan HC, Mazar AP and McMahon BJ: The apparent uPA/ PAI-1 paradox in cancer: More than meets the eye. Semin Thromb Hemost. 39:382–391. 2013. View Article : Google Scholar : PubMed/NCBI
37	Okumura Y, Kamikubo Y, Curriden SA, Wang J, Kiwada T, Futaki S, Kitagawa K and Loskutoff DJ: Kinetic analysis of the interaction between vitronectin and the urokinase receptor. J Biol Chem. 277:9395–9404. 2002. View Article : Google Scholar : PubMed/NCBI
38	Czekay RP, Aertgeerts K, Curriden SA and Loskutoff DJ: Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins. J Cell Biol. 160:781–791. 2003. View Article : Google Scholar : PubMed/NCBI
39	Balsara RD and Ploplis VA: Plasminogen activator inhibitor-1: The double-edged sword in apoptosis. Thromb Haemost. 100:1029–1036. 2008.
40	Devy L, Blacher S, Grignet-Debrus C, Bajou K, Masson V, Gerard RD, Gils A, Carmeliet G, Carmeliet P, Declerck PJ, et al: The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. FASEB J. 16:147–154. 2002. View Article : Google Scholar : PubMed/NCBI
41	Lambert V, Munaut C, Carmeliet P, Gerard RD, Declerck PJ, Gils A, Claes C, Foidart JM, Noël A and Rakic JM: Dose-dependent modulation of choroidal neovascularization by plasminogen activator inhibitor type I: Implications for clinical trials. Invest Ophthalmol Vis Sci. 44:2791–2797. 2003. View Article : Google Scholar : PubMed/NCBI
42	Bajou K, Masson V, Gerard RD, Schmitt PM, Albert V, Praus M, Lund LR, Frandsen TL, Brunner N, Dano K, et al: The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies. J Cell Biol. 152:777–784. 2001. View Article : Google Scholar : PubMed/NCBI
43	Nishioka N, Matsuoka T, Yashiro M, Hirakawa K, Olden K and Roberts JD: Plasminogen activator inhibitor 1 RNAi suppresses gastric cancer metastasis in vivo. Cancer Sci. 103:228–232. 2012. View Article : Google Scholar
44	Stefansson S, McMahon GA, Petitclerc E and Lawrence DA: Plasminogen activator inhibitor-1 in tumor growth, angiogenesis and vascular remodeling. Curr Pharm Des. 9:1545–1564. 2003. View Article : Google Scholar : PubMed/NCBI
45	Zheng D, Chen H, Davids J, Bryant M and Lucas A: Serpins for diagnosis and therapy in cancer. Cardiovasc Hematol Disord Drug Targets. 13:123–132. 2013.PubMed/NCBI
46	Kohler HP and Grant PJ: Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med. 342:1792–1801. 2000. View Article : Google Scholar : PubMed/NCBI
47	Vairaktaris E, Yapijakis C, Serefoglou Z, Vylliotis A, Ries J, Nkenke E, Wiltfang J, Derka S, Vassiliou S, Springer I, et al: Plasminogen activator inhibitor-1 polymorphism is associated with increased risk for oral cancer. Oral Oncol. 42:888–892. 2006. View Article : Google Scholar : PubMed/NCBI
48	Grunnet M, Christensen IJ, Lassen U, Jensen LH, Lydolph M, Lund IK, Thurison T, Høyer-Hansen G and Mau-Sørensen M: Prognostic significance of circulating intact and cleaved forms of urokinase plasminogen activator receptor in inoperable chemotherapy treated cholangiocarcinoma patients. Clin Biochem. 47:599–604. 2014. View Article : Google Scholar : PubMed/NCBI
49	Illemann M, Laerum OD, Hasselby JP, Thurison T, Høyer-Hansen G, Nielsen HJ and Christensen IJ; Danish Study Group on Early Detection of Colorectal Cancer. Urokinase-type plasminogen activator receptor (uPAR) on tumor-associated macrophages is a marker of poor prognosis in colorectal cancer. Cancer Med. 3:855–864. 2014. View Article : Google Scholar : PubMed/NCBI
50	Thurison T, Christensen IJ, Lund IK, Nielsen HJ and Hoyer-Hansen G: Circulating intact and cleaved forms of the urokinase-type plasminogen activator receptor: biological variation, reference intervals and clinical useful cut-points. Clin Chim Acta. 439:84–90. 2015. View Article : Google Scholar
51	Nozaki S, Endo Y, Nakahara H, Yoshizawa K, Hashiba Y, Kawashiri S, Tanaka A, Nakagawa K, Matsuoka Y, Kogo M, et al: Inhibition of invasion and metastasis in oral cancer by targeting urokinase-type plasminogen activator receptor. Oral Oncol. 41:971–977. 2005. View Article : Google Scholar : PubMed/NCBI
52	Sager R, Sheng S, Pemberton P and Hendrix MJ: Maspin. A tumor suppressing serpin. Adv Exp Med Biol. 425:77–88. 1997. View Article : Google Scholar : PubMed/NCBI
53	Sager R, Sheng S, Pemberton P and Hendrix MJ: Maspin: A tumor suppressing serpin. Curr Top Microbiol Immunol. 213:51–64. 1996.PubMed/NCBI
54	Chen EI and Yates JR III: Maspin and tumor metastasis. IUBMB Life. 58:25–29. 2006. View Article : Google Scholar : PubMed/NCBI
55	Teoh SS, Vieusseux J, Prakash M, Berkowicz S, Luu J, Bird CH, Law RH, Rosado C, Price JT, Whisstock JC, et al: Maspin is not required for embryonic development or tumour suppression. Nat Commun. 5:31642014. View Article : Google Scholar : PubMed/NCBI
56	Nozaki S, Endo Y, Kawashiri S, Nakagawa K, Yamamoto E, Yonemura Y and Sasaki T: Immunohistochemical localization of a urokinase-type plasminogen activator system in squamous cell carcinoma of the oral cavity: Association with mode of invasion and lymph node metastasis. Oral Oncol. 34:58–62. 1998. View Article : Google Scholar : PubMed/NCBI
57	Shi Z, Liu Y, Johnson JJ and Stack MS: Urinary-type plasminogen activator receptor (uPAR) modulates oral cancer cell behavior with alteration in p130cas. Mol Cell Biochem. 357:151–161. 2011. View Article : Google Scholar : PubMed/NCBI
58	Henneke I, Greschus S, Savai R, Korfei M, Markart P, Mahavadi P, Schermuly RT, Wygrecka M, Stürzebecher J, Seeger W, et al: Inhibition of urokinase activity reduces primary tumor growth and metastasis formation in a murine lung carcinoma model. Am J Respir Crit Care Med. 181:611–619. 2010. View Article : Google Scholar : PubMed/NCBI
59	Schweinitz A, Steinmetzer T, Banke IJ, Arlt MJ, Stürzebecher A, Schuster O, Geissler A, Giersiefen H, Zeslawska E, Jacob U, et al: Design of novel and selective inhibitors of urokinase-type plasminogen activator with improved pharmacokinetic properties for use as antimetastatic agents. J Biol Chem. 279:33613–33622. 2004. View Article : Google Scholar : PubMed/NCBI
60	Jankun J and Skrzypczak-Jankun E: Molecular basis of specific inhibition of urokinase plasminogen activator by amiloride. Cancer Biochem Biophys. 17:109–123. 1999.
61	Jankun J and Skrzypczak-Jankun E: Binding site of amiloride to urokinase plasminogen activator depends on species. Int J Mol Med. 8:365–371. 2001.PubMed/NCBI
62	Swiercz R, Skrzypczak-Jankun E, Merrell MM, Selman SH and Jankun J: Angiostatic activity of synthetic inhibitors of urokinase type plasminogen activator. Oncol Rep. 6:523–526. 1999.PubMed/NCBI
63	Wendt MD, Rockway TW, Geyer A, McClellan W, Weitzberg M, Zhao X, Mantei R, Nienaber VL, Stewart K, Klinghofer V, et al: Identification of novel binding interactions in the development of potent, selective 2-naphthamidine inhibitors of urokinase. Synthesis, structural analysis, and SAR of N-phenyl amide 6-substitution. J Med Chem. 47:303–324. 2004. View Article : Google Scholar : PubMed/NCBI
64	Jankun J, Keck RW and Selman SH: Epigallocatechin-3-gallate prevents tumor cell implantation/growth in an experimental rat bladder tumor model. Int J Oncol. 44:147–152. 2014.
65	Jankun J, Selman SH, Swiercz R and Skrzypczak-Jankun E: Why drinking green tea could prevent cancer. Nature. 387:5611997. View Article : Google Scholar : PubMed/NCBI
66	Jankun J, Yang J, Zheng H, Han FQ, Al-Senaidy A and Skrzypczak-Jankun E: Remarkable extension of PAI-1 half-life surprisingly brings no changes to its structure. Int J Mol Med. 29:61–64. 2012.
67	Li X, Zheng T, Sang S and Lv L: Quercetin inhibits advanced glycation end product formation by trapping methylglyoxal and glyoxal. J Agric Food Chem. 62:12152–12158. 2014. View Article : Google Scholar : PubMed/NCBI
68	Liu P, Zou D, Yi L, Chen M, Gao Y, Zhou R, Zhang Q, Zhou Y, Zhu J, Chen K, et al: Quercetin ameliorates hypobaric hypoxia-induced memory impairment through mitochondrial and neuron function adaptation via the PGC-1α pathway. Restor Neurol Neurosci. 33:143–157. 2015.
69	Lai WW, Hsu SC, Chueh FS, Chen YY, Yang JS, Lin JP, Lien JC, Tsai CH and Chung JG: Quercetin inhibits migration and invasion of SAS human oral cancer cells through inhibition of NF-κB and matrix metalloproteinase-2/-9 signaling pathways. Anticancer Res. 33:1941–1950. 2013.PubMed/NCBI
70	Manolova Y, Deneva V, Antonov L, Drakalska E, Momekova D and Lambov N: The effect of the water on the curcumin tautomerism: A quantitative approach. Spectrochim Acta A Mol Biomol Spectrosc. 132:815–820. 2014. View Article : Google Scholar : PubMed/NCBI
71	Strimpakos AS and Sharma RA: Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials. Antioxid Redox Signal. 10:511–545. 2008. View Article : Google Scholar : PubMed/NCBI
72	Hatcher H, Planalp R, Cho J, Torti FM and Torti SV: Curcumin: From ancient medicine to current clinical trials. Cell Mol Life Sci. 65:1631–1652. 2008. View Article : Google Scholar : PubMed/NCBI
73	Zhen L, Fan D, Yi X, Cao X, Chen D and Wang L: Curcumin inhibits oral squamous cell carcinoma proliferation and invasion via EGFR signaling pathways. Int J Clin Exp Pathol. 7:6438–6446. 2014.PubMed/NCBI
74	Li MJ, Yin YC, Wang J and Jiang YF: Green tea compounds in breast cancer prevention and treatment. World J Clin Oncol. 5:520–528. 2014. View Article : Google Scholar : PubMed/NCBI
75	Yang CS, Chen G and Wu Q: Recent scientific studies of a traditional chinese medicine, tea, on prevention of chronic diseases. J Tradit Complement Med. 4:17–23. 2014. View Article : Google Scholar : PubMed/NCBI
76	Yiannakopoulou EC: Green tea catechins: Proposed mechanisms of action in breast cancer focusing on the interplay between survival and apoptosis. Anticancer Agents Med Chem. 14:290–295. 2014. View Article : Google Scholar
77	Ho YC, Yang SF, Peng CY, Chou MY and Chang YC: Epigallocatechin-3-gallate inhibits the invasion of human oral cancer cells and decreases the productions of matrix metalloproteinases and urokinase-plasminogen activator. J Oral Pathol Med. 36:588–593. 2007. View Article : Google Scholar : PubMed/NCBI
78	Miocinovic R, McCabe NP, Keck RW, Jankun J, Hampton JA and Selman SH: In vivo and in vitro effect of baicalein on human prostate cancer cells. Int J Oncol. 26:241–246. 2005.
79	Yan X, Rui X and Zhang K: Baicalein inhibits the invasion of gastric cancer cells by suppressing the activity of the p38 signaling pathway. Oncol Rep. 33:737–743. 2015.
80	Zheng YH, Yin LH, Grahn TH, Ye AF, Zhao YR and Zhang QY: Anticancer effects of baicalein on hepatocellular carcinoma cells. Phytother Res. 28:1342–1348. 2014. View Article : Google Scholar : PubMed/NCBI
81	Shukla S and Gupta S: Apigenin: A promising molecule for cancer prevention. Pharm Res. 27:962–978. 2010. View Article : Google Scholar : PubMed/NCBI
82	Yang SF, Yang WE, Kuo WH, Chang HR, Chu SC and Hsieh YS: Antimetastatic potentials of flavones on oral cancer cell via an inhibition of matrix-degrading proteases. Arch Oral Biol. 53:287–294. 2008. View Article : Google Scholar
83	Brown NJ: Therapeutic potential of plasminogen activator inhibitor-1 inhibitors. Ther Adv Cardiovasc Dis. 4:315–324. 2010. View Article : Google Scholar : PubMed/NCBI
84	Rouch A, Vanucci-Bacqué C, Bedos-Belval F and Baltas M: Small molecules inhibitors of plasminogen activator inhibitor-1: an overview. Eur J Med Chem. 92:619–636. 2015. View Article : Google Scholar : PubMed/NCBI
85	Gorlatova NV, Cale JM, Elokdah H, Li D, Fan K, Warnock M, Crandall DL and Lawrence DA: Mechanism of inactivation of plasminogen activator inhibitor-1 by a small molecule inhibitor. J Biol Chem. 282:9288–9296. 2007. View Article : Google Scholar : PubMed/NCBI
86	Jankun J, Al-Senaidy A and Skrzypczak-Jankun E: Can inactivators of plasminogen activator inhibitor alleviate the burden of obesity and diabetes? (Review). Int J Mol Med. 29:3–11. 2012.
87	Naessens D, Gils A, Compernolle G and Declerck PJ: Elucidation of a novel epitope of a substrate-inducing monoclonal antibody against the serpin PAI-1. J Thromb Haemost. 1:1028–1033. 2003. View Article : Google Scholar : PubMed/NCBI
88	Verhamme I, Kvassman JO, Day D, Debrock S, Vleugels N, Declerck PJ and Shore JD: Accelerated conversion of human plasminogen activator inhibitor-1 to its latent form by antibody binding. J Biol Chem. 274:17511–17517. 1999. View Article : Google Scholar : PubMed/NCBI
89	Egelund R, Einholm AP, Pedersen KE, Nielsen RW, Christensen A, Deinum J and Andreasen PA: A regulatory hydrophobic area in the flexible joint region of plasminogen activator inhibitor-1, defined with fluorescent activity-neutralizing ligands. Ligand-induced serpin polymerization. J Biol Chem. 276:13077–13086. 2001. View Article : Google Scholar : PubMed/NCBI
90	Crandall DL, Elokdah H, Di L, Hennan JK, Gorlatova NV and Lawrence DA: Characterization and comparative evaluation of a structurally unique PAI-1 inhibitor exhibiting oral in-vivo efficacy. J Thromb Haemost. 2:1422–1428. 2004. View Article : Google Scholar : PubMed/NCBI
91	Gardell SJ, Krueger JA, Antrilli TA, Elokdah H, Mayer S, Orcutt SJ, Crandall DL and Vlasuk GP: Neutralization of plasminogen activator inhibitor I (PAI-1) by the synthetic antagonist PAI-749 via a dual mechanism of action. Mol Pharmacol. 72:897–906. 2007. View Article : Google Scholar : PubMed/NCBI
92	Jankun J, Skotnicka M, Łysiak-Szydłowska W, Al-Senaidy A and Skrzypczak-Jankun E: Diverse inhibition of plasminogen activator inhibitor type 1 by theaflavins of black tea. Int J Mol Med. 27:525–529. 2011. View Article : Google Scholar : PubMed/NCBI
93	Zhang YF, Xu Q, Lu J, Wang P, Zhang HW, Zhou L, Ma XQ and Zhou YH: Tea consumption and the incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Eur J Cancer Prev. Nov 3–2014.(Epub ahead of print). View Article : Google Scholar
94	Lee MJ, Lambert JD, Prabhu S, Meng X, Lu H, Maliakal P, Ho CT and Yang CS: Delivery of tea polyphenols to the oral cavity by green tea leaves and black tea extract. Cancer Epidemiol Biomarkers Prev. 13:132–137. 2004. View Article : Google Scholar : PubMed/NCBI
95	Yang CS, Maliakal P and Meng X: Inhibition of carcinogenesis by tea. Annu Rev Pharmacol Toxicol. 42:25–54. 2002. View Article : Google Scholar : PubMed/NCBI
96	Ghosh S, Johnson JJ, Sen R, Mukhopadhyay S, Liu Y, Zhang F, Wei Y, Chapman HA and Stack MS: Functional relevance of urinary-type plasminogen activator receptor-alpha3beta1 integrin association in proteinase regulatory pathways. J Biol Chem. 281:13021–13029. 2006. View Article : Google Scholar : PubMed/NCBI
97	Lee EJ, Whang JH, Jeon NK and Kim J: The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses proliferation and invasion of human oral squamous carcinoma cells via p53 independent and MMP, uPAR dependent mechanism. Ann NY Acad Sci. 1095:113–128. 2007. View Article : Google Scholar : PubMed/NCBI
98	Liang X, Yang X, Tang Y, Zhou H, Liu X, Xiao L, Gao J and Mao Z: RNAi-mediated downregulation of urokinase plasminogen activator receptor inhibits proliferation, adhesion, migration and invasion in oral cancer cells. Oral Oncol. 44:1172–1180. 2008. View Article : Google Scholar : PubMed/NCBI
99	Pasini FS, Brentani MM, Kowalski LP and Federico MH: Transforming growth factor beta1, urokinase-type plasminogen activator and plasminogen activator inhibitor-1 mRNA expression in head and neck squamous carcinoma and normal adjacent mucosa. Head Neck. 23:725–732. 2001. View Article : Google Scholar : PubMed/NCBI
100	Vairaktaris E, Serefoglou Z, Avgoustidis D, Yapijakis C, Critselis E, Vylliotis A, Spyridonidou S, Derka S, Vassiliou S, Nkenke E, et al: Gene polymorphisms related to angiogenesis, inflammation and thrombosis that influence risk for oral cancer. Oral Oncol. 45:247–253. 2009. View Article : Google Scholar
101	Hercberg S, Kesse-Guyot E, Druesne-Pecollo N, Touvier M, Favier A, Latino-Martel P, Briançon S and Galan P: Incidence of cancers, ischemic cardiovascular diseases and mortality during 5-year follow-up after stopping antioxidant vitamins and minerals supplements: a postintervention follow-up in the SU.VI.MAX Study. Int J Cancer. 127:1875–1881. 2010. View Article : Google Scholar : PubMed/NCBI
102	Press OA, Zhang W, Gordon MA, Yang D, Lurje G, Iqbal S, El-Khoueiry A and Lenz HJ: Gender-related survival differences associated with EGFR polymorphisms in metastatic colon cancer. Cancer Res. 68:3037–3042. 2008. View Article : Google Scholar : PubMed/NCBI
103	Nainani P, Paliwal A, Nagpal N and Agrawal M: Sex hormones in gender-specific risk for head and neck cancer: A review. J Int Soc Prev Community Dent. 4(Suppl 1): S1–S4. 2014. View Article : Google Scholar : PubMed/NCBI
104	Wang YJ, Pan MH, Cheng AL, Lin LI, Ho YS, Hsieh CY and Lin JK: Stability of curcumin in buffer solutions and characterization of its degradation products. J Pharm Biomed Anal. 15:1867–1876. 1997. View Article : Google Scholar : PubMed/NCBI
105	Stout TJ, Graham H, Buckley DI and Matthews DJ: Structures of active and latent PAI-1: A possible stabilizing role for chloride ions. Biochemistry. 39:8460–8469. 2000. View Article : Google Scholar : PubMed/NCBI
106	Zeslawska E, Jacob U, Schweinitz A, Coombs G, Bode W and Madison E: Crystals of urokinase type plasminogen activator complexes reveal the binding mode of peptidomimetic inhibitors. J Mol Biol. 328:109–118. 2003. View Article : Google Scholar : PubMed/NCBI
107	Li SH, Reinke AA, Sanders KL, Emal CD, Whisstock JC, Stuckey JA and Lawrence DA: Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1. Proc Natl Acad Sci USA. 110:E4941–E4949. 2013. View Article : Google Scholar : PubMed/NCBI
108	Shen L and Ji HF: Contribution of degradation products to the anticancer activity of curcumin. Clin Cancer Res. 15:7108author reply 7108–7109. 2009. View Article : Google Scholar : PubMed/NCBI