Decreased expression of the plasminogen activator inhibitor type 1 is involved in degradation of extracellular matrix surrounding cervical cancer stem cells

Sato,Masakazu; Kawana,Kei; Adachi,Katsuyuki; Fujimoto,Asaha; Yoshida,Mitsuyo; Nakamura,Hiroe; Nishida,Haruka; Inoue,Tomoko; Taguchi,Ayumi; Takahashi,Juri; Kojima,Satoko; Yamashita,Aki; Tomio,Kensuke; Nagamatsu,Takeshi; Wada-Hiraike,Osamu; Oda,Katsutoshi; Osuga,Yutaka; Fujii,Tomoyuki

doi:10.3892/ijo.2015.3283

Decreased expression of the plasminogen activator inhibitor type 1 is involved in degradation of extracellular matrix surrounding cervical cancer stem cells

Authors:
- Masakazu Sato
- Kei Kawana
- Katsuyuki Adachi
- Asaha Fujimoto
- Mitsuyo Yoshida
- Hiroe Nakamura
- Haruka Nishida
- Tomoko Inoue
- Ayumi Taguchi
- Juri Takahashi
- Satoko Kojima
- Aki Yamashita
- Kensuke Tomio
- Takeshi Nagamatsu
- Osamu Wada-Hiraike
- Katsutoshi Oda
- Yutaka Osuga
- Tomoyuki Fujii
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Affiliations: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Published online on: December 9, 2015 https://doi.org/10.3892/ijo.2015.3283
Pages: 829-835

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Abstract

The plasminogen activator (PA) system consists of plasminogen activator inhibitor type 1 (PAI-1), urokinase-type plasminogen activator and its receptor (uPA and uPAR). PAI-1 inhibits the activation of uPA (which converts plasminogen to plasmin), and is involved in cancer invasion and metastasis, by remodeling the extracellular matrix (ECM) through regulating plasmin. Cancer stem cells (CSCs) are a small subset of cells within tumors, and are thought to be involved in tumor recurrence and metastasis. Considering these facts, we investigated the relationship between PAI-1 and cervical CSCs. We used ALDH1 as a marker of cervical CSCs. First, we demonstrated that culturing ALDH1-high cells and ALDH-low cells on collagen IV-coted plates increased their expression of active PAI-1 (ELISA), and these increases were suggested to be at mRNA expression levels (RT-qPCR). Secondly, we demonstrated PAI-1 was indeed involved in the ECM maintenance. With gelatin zymography assays, we found that ALDH1-high cells and ALDH-low cells expressed pro-matrix metalloproteinase-2 (pro-MMP-2) irrespective of their coatings. With gelatinase/collagenase assay kit, we confirmed that collagenase activity was increased when ALDH1-low cells were exposed to TM5275, a small molecule inhibitor of PAI-1. Putting the data together, we hypothesized that cancer cells adhered to basal membrane secrete abundant PAI-1, on the other hand, cancer cells (especially CSCs rather than non-CSCs) distant from basal membrane secrete less PAI-1, which makes the ECM surrounding CSCs more susceptible to degradation. Our study could be an explanation of conflicting reports, where some researchers found negative impacts of PAI-1 expression on clinical outcomes and others not, by considering the concept of CSCs.

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1	Czekay RP, Wilkins-Port CE, Higgins SP, Freytag J, Overstreet JM, Klein RM, Higgins CE, Samarakoon R and Higgins PJ: PAI-1: An integrator of cell signaling and migration. Int J Cell Biol. 2011:5624812011. View Article : Google Scholar : PubMed/NCBI
2	Jankun J: Plasminogen activator inhibitor-1 in kidney pathology (Review). Int J Mol Med. 31:503–510. 2013.PubMed/NCBI
3	Klinger KW, Winqvist R, Riccio A, Andreasen PA, Sartorio R, Nielsen LS, Stuart N, Stanislovitis P, Watkins P, Douglas R, et al: Plasminogen activator inhibitor type 1 gene is located at region q21.3-q22 of chromosome 7 and genetically linked with cysticfibrosis. Proc Natl Acad Sci USA. 84:8548–8552. 1987. View Article : Google Scholar
4	Krause MP, Moradi J, Nissar AA, Riddell MC and Hawke TJ: Inhibition of plasminogen activator inhibitor-1 restores skeletal muscle regeneration in untreated type 1 diabetic mice. Diabetes. 60:1964–1972. 2011. View Article : Google Scholar : PubMed/NCBI
5	Ricart JM, Ramón LA, Vayá A, España F, Santaolaria ML, Todolí J, Castelló R, Fontcuberta J and Estellés A: Fibrinolytic inhibitor levels and polymorphisms in Behcet disease and their association with thrombosis. Br J Haematol. 141:716–719. 2008. View Article : Google Scholar : PubMed/NCBI
6	Bajou K, Noël A, Gerard RD, Masson V, Brunner N, Holst-Hansen C, Skobe M, Fusenig NE, Carmeliet P, Collen D, et al: Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med. 4:923–928. 1998. View Article : Google Scholar : PubMed/NCBI
7	Fabre-Guillevin E, Malo M, Cartier-Michaud A, Peinado H, Moreno-Bueno G, Vallée B, Lawrence DA, Palacios J, Cano A, Barlovatz-Meimon G, et al: PAI-1 and functional blockade of SNAI1 in breast cancer cell migration. Breast Cancer Res. 10:R1002008. View Article : Google Scholar : PubMed/NCBI
8	Smit JW, van der Pluijm G, Romijn HA, Löwik CW, Morreau H and Goslings BM: Degradation of extracellular matrix by metastatic follicular thyroid carcinoma cell lines: role of the plasmin activation system. Thyroid. 9:913–919. 1999. View Article : Google Scholar : PubMed/NCBI
9	Maillard C, Jost M, Rømer MU, Brunner N, Houard X, Lejeune A, Munaut C, Bajou K, Melen L, Dano K, et al: Host plasminogen activator inhibitor-1 promotes human skin carcinoma progression in a stage-dependent manner. Neoplasia. 7:57–66. 2005. View Article : Google Scholar : PubMed/NCBI
10	Riddick AC, Shukla CJ, Pennington CJ, Bass R, Nuttall RK, Hogan A, Sethia KK, Ellis V, Collins AT, Maitland NJ, et al: Identification of degradome components associated with prostate cancer progression by expression analysis of human prostatic tissues. Br J Cancer. 92:2171–2180. 2005. View Article : Google Scholar : PubMed/NCBI
11	Vial D and McKeown-Longo PJ: PAI1 stimulates assembly of the fibronectin matrix in osteosarcoma cells through crosstalk between the alphavbeta5 and alpha5beta1 integrins. J Cell Sci. 121:1661–1670. 2008. View Article : Google Scholar : PubMed/NCBI
12	Woo M, Park K, Nam J and Kim JC: Clinical implications of matrix metalloproteinase-1, -3, -7, -9, -12, and plasminogen activator inhibitor-1 gene polymorphisms in colorectal cancer. J Gastroenterol Hepatol. 22:1064–1070. 2007. View Article : Google Scholar : PubMed/NCBI
13	Hanekom GS, Stubbings HM and Kidson SH: The active fraction of plasmatic plasminogen activator inhibitor type 1 as a possible indicator of increased risk for metastatic melanoma. Cancer Detect Prev. 26:50–59. 2002. View Article : Google Scholar : PubMed/NCBI
14	Lara PC, Lloret M, Valenciano A, Clavo B, Pinar B, Rey A and Henríquez-Hernández LA: Plasminogen activator inhibitor-1 (PAI-1) expression in relation to hypoxia and oncoproteins in clinical cervical tumors. Strahlenther Onkol. 188:1139–1145. 2012. View Article : Google Scholar : PubMed/NCBI
15	Malinowsky K, Wolff C, Berg D, Schuster T, Walch A, Bronger H, Mannsperger H, Schmidt C, Korf U, Höfler H, et al: uPA and PAI-1-related signaling pathways differ between primary breast cancers and lymph node metastases. Transl Oncol. 5:98–104. 2012. View Article : Google Scholar : PubMed/NCBI
16	Sternlicht MD, Dunning AM, Moore DH, Pharoah PD, Ginzinger DG, Chin K, Gray JW, Waldman FM, Ponder BA and Werb Z: Prognostic value of PAI1 in invasive breast cancer: evidence that tumor-specific factors are more important than genetic variation in regulating PAI1 expression. Cancer Epidemiol Biomarkers Prev. 15:2107–2114. 2006. View Article : Google Scholar : PubMed/NCBI
17	Meacham CE and Morrison SJ: Tumour heterogeneity and cancer cell plasticity. Nature. 501:328–337. 2013. View Article : Google Scholar : PubMed/NCBI
18	Reya T, Morrison SJ, Clarke MF and Weissman IL: Stem cells, cancer, and cancer stem cells. Nature. 414:105–111. 2001. View Article : Google Scholar : PubMed/NCBI
19	Chen X, Rycaj K, Liu X and Tang DG: New insights into prostate cancer stem cells. Cell Cycle. 12:579–586. 2013. View Article : Google Scholar : PubMed/NCBI
20	Dick JE: Stem cell concepts renew cancer research. Blood. 112:4793–4807. 2008. View Article : Google Scholar : PubMed/NCBI
21	López J, Valdez-Morales FJ, Benítez-Bribiesca L, Cerbón M and Carrancá AG: Normal and cancer stem cells of the human female reproductive system. Reprod Biol Endocrinol. 11:532013. View Article : Google Scholar : PubMed/NCBI
22	Skibinski A and Kuperwasser C: The origin of breast tumor heterogeneity. Oncogene. 34:5309–5316. 2015. View Article : Google Scholar : PubMed/NCBI
23	Triscott J, Rose Pambid M and Dunn SE: Concise review: bullseye: targeting cancer stem cells to improve the treatment of gliomas by repurposing disulfiram. Stem Cells. 33:1042–1046. 2015. View Article : Google Scholar : PubMed/NCBI
24	Zeki SS, Graham TA and Wright NA: Stem cells and their implications for colorectal cancer. Nat Rev Gastroenterol Hepatol. 8:90–100. 2011. View Article : Google Scholar : PubMed/NCBI
25	Hirata N, Yamada S, Shoda T, Kurihara M, Sekino Y and Kanda Y: Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation. Nat Commun. 5:48062014. View Article : Google Scholar : PubMed/NCBI
26	Alonso-Alconada L, Muinelo-Romay L, Madissoo K, Diaz-Lopez A, Krakstad C, Trovik J, Wik E, Hapangama D, Coenegrachts L, Cano A, et al: Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer. Mol Cancer. 13:2232014. View Article : Google Scholar : PubMed/NCBI
27	Ma I and Allan AL: The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem Cell Rev. 7:292–306. 2011. View Article : Google Scholar
28	Penumatsa K, Edassery SL, Barua A, Bradaric MJ and Luborsky JL: Differential expression of aldehyde dehydrogenase 1a1 (ALDH1) in normal ovary and serous ovarian tumors. J Ovarian Res. 3:282010. View Article : Google Scholar : PubMed/NCBI
29	Pisanu ME, Noto A, De Vitis C, Masiello MG, Coluccia P, Proietti S, Giovagnoli MR, Ricci A, Giarnieri E, Cucina A, et al: Lung cancer stem cell lose their stemness default state after exposure to microgravity. Biomed Res Int. 2014:4702532014. View Article : Google Scholar : PubMed/NCBI
30	Pors K and Moreb JS: Aldehyde dehydrogenases in cancer: An opportunity for biomarker and drug development? Drug Discov Today. 19:1953–1963. 2014. View Article : Google Scholar : PubMed/NCBI
31	Raha D, Wilson TR, Peng J, Peterson D, Yue P, Evangelista M, Wilson C, Merchant M and Settleman J: The cancer stem cell marker aldehyde dehydrogenase is required to maintain a drug-tolerant tumor cell subpopulation. Cancer Res. 74:3579–3590. 2014. View Article : Google Scholar : PubMed/NCBI
32	Warrier S, Bhuvanalakshmi G, Arfuso F, Rajan G, Millward M and Dharmarajan A: Cancer stem-like cells from head and neck cancers are chemosensitized by the Wnt antagonist, sFRP4, by inducing apoptosis, decreasing stemness, drug resistance and epithelial to mesenchymal transition. Cancer Gene Ther. 21:381–388. 2014. View Article : Google Scholar : PubMed/NCBI
33	Watanabe Y, Yoshimura K, Yoshikawa K, Tsunedomi R, Shindo Y, Matsukuma S, Maeda N, Kanekiyo S, Suzuki N, Kuramasu A, et al: A stem cell medium containing neural stimulating factor induces a pancreatic cancer stem-like cell-enriched population. Int J Oncol. 45:1857–1866. 2014.PubMed/NCBI
34	Liu SY and Zheng PS: High aldehyde dehydrogenase activity identifies cancer stem cells in human cervical cancer. Oncotarget. 4:2462–2475. 2013. View Article : Google Scholar : PubMed/NCBI
35	Isogai C, Laug WE, Shimada H, Declerck PJ, Stins MF, Durden DL, Erdreich-Epstein A and DeClerck YA: Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin. Cancer Res. 61:5587–5594. 2001.PubMed/NCBI
36	Taguchi A, Kawana K, Tomio K, Yamashita A, Isobe Y, Nagasaka K, Koga K, Inoue T, Nishida H, Kojima S, et al: Matrix metalloproteinase (MMP)-9 in cancer-associated fibroblasts (CAFs) is suppressed by omega-3 polyunsaturated fatty acids in vitro and in vivo. PLoS One. 9:e896052014. View Article : Google Scholar : PubMed/NCBI
37	Goldberg I, Davidson B, Lerner-Geva L, Gotlieb WH, Ben-Baruch G, Novikov I and Kopolovic J: Expression of extracellular matrix proteins in cervical squamous cell carcinoma - a clinicopathological study. J Clin Pathol. 51:781–785. 1998. View Article : Google Scholar
38	Han B, Nakamura M, Zhou G, Ishii A, Nakamura A, Bai Y, Mori I and Kakudo K: Calcitonin inhibits invasion of breast cancer cells: Involvement of urokinase-type plasminogen activator (uPA) and uPA receptor. Int J Oncol. 28:807–814. 2006.PubMed/NCBI
39	Hildenbrand R and Schaaf A: The urokinase-system in tumor tissue stroma of the breast and breast cancer cell invasion. Int J Oncol. 34:15–23. 2009.
40	Roomi MW, Kalinovsky T, Niedzwiecki A and Rath M: Modulation of uPA, MMPs and their inhibitors by a novel nutrient mixture in human glioblastoma cell lines. Int J Oncol. 45:887–894. 2014.PubMed/NCBI
41	Chung CL, Sheu JR, Liu HE, Chang SC, Chou YC, Chen WL, Chou DS and Hsiao G: Dynasore, a dynamin inhibitor, induces PAI-1 expression in MeT-5A human pleural mesothelial cells. Am J Respir Cell Mol Biol. 40:692–700. 2009. View Article : Google Scholar
42	Baramova EN, Bajou K, Remacle A, L'Hoir C, Krell HW, Weidle UH, Noel A and Foidart JM: Involvement of PA/plasmin system in the processing of pro-MMP-9 and in the second step of pro-MMP-2 activation. FEBS Lett. 405:157–162. 1997. View Article : Google Scholar : PubMed/NCBI
43	Izuhara Y, Yamaoka N, Kodama H, Dan T, Takizawa S, Hirayama N, Meguro K, van Ypersele de Strihou C and Miyata T: A novel inhibitor of plasminogen activator inhibitor-1 provides antithrombotic benefits devoid of bleeding effect in nonhuman primates. J Cereb Blood Flow Metab. 30:904–912. 2010. View Article : Google Scholar : PubMed/NCBI
44	Marchina E and Barlati S: Degradation of human plasma and extracellular matrix fibronectin by tissue type plasminogen activator and urokinase. Int J Biochem Cell Biol. 28:1141–1150. 1996. View Article : Google Scholar : PubMed/NCBI
45	Ota H, Akishita M, Eto M, Iijima K, Kaneki M and Ouchi Y: Sirt1 modulates premature senescence-like phenotype in human endothelial cells. J Mol Cell Cardiol. 43:571–579. 2007. View Article : Google Scholar : PubMed/NCBI
46	Calvanese V, Lara E, Suárez-Alvarez B, Abu Dawud R, Vázquez-Chantada M, Martínez-Chantar ML, Embade N, López-Nieva P, Horrillo A, Hmadcha A, et al: Sirtuin 1 regulation of developmental genes during differentiation of stem cells. Proc Natl Acad Sci USA. 107:13736–13741. 2010. View Article : Google Scholar : PubMed/NCBI
47	Wan YZ, Gao P, Zhou S, Zhang ZQ, Hao DL, Lian LS, Li YJ, Chen HZ and Liu DP: SIRT1-mediated epigenetic downregulation of plasminogen activator inhibitor-1 prevents vascular endothelial replicative senescence. Aging Cell. 13:890–899. 2014. View Article : Google Scholar : PubMed/NCBI