Generic placeholder image

Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Research Article

Assessment of the Usefulness of the SEMA5A Concentration Profile Changes as a Molecular Marker in Endometrial Cancer

Author(s): Konrad Dziobek*, Marcin Opławski, Beniamin O. Grabarek, Nikola Zmarzły, Przemysław Kieszkowski, Piotr Januszyk, Kamil Kiełbasiński, Robert Kiełbasiński and Dariusz Boroń

Volume 21, Issue 1, 2020

Page: [45 - 51] Pages: 7

DOI: 10.2174/1389201020666190911113611

Price: $65

Abstract

Background: Semaphorin 5A (SEMA5A) functions not only in the nervous system but also in cancer transformation where its role has not yet been sufficiently studied and described.

Objective: The aim of the study was to determine the changes in SEMA5A expression in endometrial cancer at various degrees of its differentiation (G1-G3) compared to control.

Materials and Methods: The study group consisted of 45 patients with endometrial cancer at various grades: G1, 17; G2, 15; G3, 13. The control consisted of 15 women without neoplastic changes in the routine gynecological examination. The statistical analysis of immunohistochemical assessment of SEMA5A level was carried out using the Statistica 12 program based on the Kruskal-Wallis test and Dunn’s post-hoc test (p<0.05).

Results: The expression of SEMA5A (optical density) was observed in the control group (Me = 103.43) and in the study group (G1, Me = 140.72; G2, Me = 150.88; G3, Me = 173.77). Differences in expression between each grade and control and between individual grades turned out to be statistically significant (p<0.01). The protein level of SEMA5A expression increased with the decreasing degree of endometrial cancer differentiation.

Conclusion: In our research, we indicated the overexpression of SEMA5A protein in endometrial cancer. It is a valuable starting point for further consideration of the role of SEMA5A as a new supplementary molecular marker in endometrial cancer.

Keywords: SEMA5A, angiogenesis, endometrial cancer, molecular marker, JAK/STAT signaling pathway, gynecological examination.

Graphical Abstract
[1]
Folkman, J. Angiogenesis. Annu. Rev. Med., 2006, 57, 1-18.
[http://dx.doi.org/10.1146/annurev.med.57.121304.131306] [PMID: 16409133]
[2]
Viallard, C.; Larrivée, B. Tumor angiogenesis and vascular normalization: Alternative therapeutic targets. Angiogenesis, 2017, 20(4), 409-426.
[http://dx.doi.org/10.1007/s10456-017-9562-9] [PMID: 28660302]
[3]
Ronca, R.; Benkheil, M.; Mitola, S.; Struyf, S.; Liekens, S. Tumor angiogenesis revisited: Regulators and clinical implications. Med. Res. Rev., 2017, 37(6), 1231-1274.
[http://dx.doi.org/10.1002/med.21452] [PMID: 28643862]
[4]
Carmeliet, P.; Jain, R.K. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat. Rev. Drug Discov., 2011, 10(6), 417-427.
[http://dx.doi.org/10.1038/nrd3455] [PMID: 21629292]
[5]
Corzo, C.A.; Condamine, T.; Lu, L.; Cotter, M.J.; Youn, J.I.; Cheng, P.; Cho, H.I.; Celis, E.; Quiceno, D.G.; Padhya, T.; McCaffrey, T.V.; McCaffrey, J.C.; Gabrilovich, D.I. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J. Exp. Med., 2010, 207(11), 2439-2453.
[http://dx.doi.org/10.1084/jem.20100587] [PMID: 20876310]
[6]
Jain, R.K. Antiangiogenesis strategies revisited: From starving tumors to alleviating hypoxia. Cancer Cell, 2014, 26(5), 605-622.
[http://dx.doi.org/10.1016/j.ccell.2014.10.006] [PMID: 25517747]
[7]
Carmeliet, P.; Jain, R.K. Molecular mechanisms and clinical applications of angiogenesis. Nature, 2011, 473(7347), 298-307.
[http://dx.doi.org/10.1038/nature10144] [PMID: 21593862]
[8]
Amani, H.; Ajami, M.; Nasseri Maleki, S.; Pazoki-Toroudi, H.; Daglia, M.; Tsetegho Sokeng, A.J.; Di Lorenzo, A.; Nabavi, S.F.; Devi, K.P.; Nabavi, S.M. Targeting signal transducers and activators of transcription (STAT) in human cancer by dietary polyphenolic antioxidants. Biochimie, 2017, 142, 63-79.
[http://dx.doi.org/10.1016/j.biochi.2017.08.007] [PMID: 28807562]
[9]
Ellis, L.M. The role of neuropilins in cancer. Mol. Cancer Ther., 2006, 5(5), 1099-1107.
[http://dx.doi.org/10.1158/1535-7163.MCT-05-0538] [PMID: 16731741]
[10]
Bielenberg, D.R.; Hida, Y.; Shimizu, A.; Kaipainen, A.; Kreuter, M.; Kim, C.C.; Klagsbrun, M. Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J. Clin. Invest., 2004, 114(9), 1260-1271.
[http://dx.doi.org/10.1172/JCI21378] [PMID: 15520858]
[11]
Favier, B.; Alam, A.; Barron, P.; Bonnin, J.; Laboudie, P.; Fons, P.; Mandron, M.; Herault, J.P.; Neufeld, G.; Savi, P.; Herbert, J.M.; Bono, F. Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration. Blood, 2006, 108(4), 1243-1250.
[http://dx.doi.org/10.1182/blood-2005-11-4447] [PMID: 16621967]
[12]
Banu, N.; Teichman, J.; Dunlap-Brown, M.; Villegas, G.; Tufro, A. Semaphorin 3C regulates endothelial cell function by increasing integrin activity. FASEB J., 2006, 20(12), 2150-2152.
[http://dx.doi.org/10.1096/fj.05-5698fje] [PMID: 16940438]
[13]
Conrotto, P.; Valdembri, D.; Corso, S.; Serini, G.; Tamagnone, L.; Comoglio, P.M.; Bussolino, F.; Giordano, S. Sema4D induces angiogenesis through Met recruitment by Plexin B1. Blood, 2005, 105(11), 4321-4329.
[http://dx.doi.org/10.1182/blood-2004-07-2885] [PMID: 15632204]
[14]
Kantor, D.B.; Chivatakarn, O.; Peer, K.L.; Oster, S.F.; Inatani, M.; Hansen, M.J.; Flanagan, J.G.; Yamaguchi, Y.; Sretavan, D.W.; Giger, R.J.; Kolodkin, A.L. Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans. Neuron, 2004, 44(6), 961-975.
[http://dx.doi.org/10.1016/j.neuron.2004.12.002] [PMID: 15603739]
[15]
Liu, Y.; Wu, C.; Wang, Y.; Wen, S.; Wang, J.; Chen, Z.; He, Q.; Feng, D. Loss of plexin-B3 in hepatocellular carcinoma. Exp. Ther. Med., 2015, 9(4), 1247-1252.
[http://dx.doi.org/10.3892/etm.2015.2243] [PMID: 25780417]
[16]
Allen, E.; Jabouille, A.; Rivera, L.B.; Lodewijckx, I.; Missiaen, R.; Steri, V.; Feyen, K.; Tawney, J.; Hanahan, D.; Michael, I.P.; Bergers, G. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl. Med., 2017, 9(385) eaak9679
[http://dx.doi.org/10.1126/scitranslmed.aak9679] [PMID: 28404866]
[17]
Kuusk, T.; Albiges, L.; Escudier, B.; Grivas, N.; Haanen, J.; Powles, T.; Bex, A. Antiangiogenic therapy combined with immune checkpoint blockade in renal cancer. Angiogenesis, 2017, 20(2), 205-215.
[http://dx.doi.org/10.1007/s10456-017-9550-0] [PMID: 28401381]
[18]
Netea, M.G.; Balkwill, F.; Chonchol, M.; Cominelli, F.; Donath, M.Y.; Giamarellos-Bourboulis, E.J.; Golenbock, D.; Gresnigt, M.S.; Heneka, M.T.; Hoffman, H.M.; Hotchkiss, R.; Joosten, L.A.B.; Kastner, D.L.; Korte, M.; Latz, E.; Libby, P.; Mandrup-Poulsen, T.; Mantovani, A.; Mills, K.H.G.; Nowak, K.L.; O’Neill, L.A.; Pickkers, P.; van der Poll, T.; Ridker, P.M.; Schalkwijk, J.; Schwartz, D.A.; Siegmund, B.; Steer, C.J.; Tilg, H.; van der Meer, J.W.M.; van de Veerdonk, F.L.; Dinarello, C.A. A guiding map for inflammation. Nat. Immunol., 2017, 18(8), 826-831.
[http://dx.doi.org/10.1038/ni.3790] [PMID: 28722720]
[19]
Bosman, F.; Yan, P. Molecular pathology of colorectal cancer. Pol. J. Pathol., 2014, 65(4), 257-266.
[http://dx.doi.org/10.5114/pjp.2014.48094] [PMID: 25693079]
[20]
Zänker, M.; Becher, G.; Arbach, O.; Maurer, M.; Stuhlmüller, B.; Schäfer, A.; Strohner, P.; Brand, J. Improved adalimumab dose decision with comprehensive diagnostics data. Clin. Exp. Rheumatol., 2018, 36(1), 136-139.
[PMID: 28850025]
[21]
Negishi, M.; Oinuma, I.; Katoh, H. Plexins: Axon guidance and signal transduction. Cell. Mol. Life Sci., 2005, 62(12), 1363-1371.
[http://dx.doi.org/10.1007/s00018-005-5018-2] [PMID: 15818466]
[22]
Purohit, A.; Sadanandam, A.; Myneni, P.; Singh, R.K. Semaphorin 5A mediated cellular navigation: Connecting nervous system and cancer. Biochim. Biophys. Acta, 2014, 1846(2), 485-493.
[http://dx.doi.org/10.1016/j.bbcan.2014.09.006] [PMID: 25263940]
[23]
Neufeld, G.; Mumblat, Y.; Smolkin, T.; Toledano, S.; Nir-Zvi, I.; Ziv, K.; Kessler, O. The role of the semaphorins in cancer. Cell Adhes. Migr., 2016, 10(6), 652-674.
[http://dx.doi.org/10.1080/19336918.2016.1197478] [PMID: 27533782]
[24]
Neufeld, G.; Sabag, A.D.; Mumblat, Y.; Smolkin, T.; Kessler, O. Regulation of angiogenesis and tumor progression by semaphorins. In: Atsushi Kumanogoh (Eds.). Semaphorins 2015, 107-135.
[http://dx.doi.org/10.1007/978-4-431-54385-5_6]
[25]
Sadanandam, A.; Varney, M.L.; Singh, S.; Ashour, A.E.; Moniaux, N.; Deb, S.; Lele, S.M.; Batra, S.K.; Singh, R.K. High gene expression of semaphorin 5A in pancreatic cancer is associated with tumor growth, invasion and metastasis. Int. J. Cancer, 2010, 127(6), 1373-1383.
[http://dx.doi.org/10.1002/ijc.25166] [PMID: 20073063]
[26]
Sadanandam, A.; Sidhu, S.S.; Wullschleger, S.; Singh, S.; Varney, M.L.; Yang, C.S.; Ashour, A.E.; Batra, S.K.; Singh, R.K. Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation. Br. J. Cancer, 2012, 107(3), 501-507.
[http://dx.doi.org/10.1038/bjc.2012.298] [PMID: 22782341]
[27]
Pan, G.; Zhang, X.; Ren, J.; Lu, J.; Li, W.; Fu, H.; Zhang, S.; Li, J. Semaphorin 5A, an axon guidance molecule, enhances the invasion and metastasis of human gastric cancer through activation of MMP9. Pathol. Oncol. Res., 2013, 19(1), 11-18.
[http://dx.doi.org/10.1007/s12253-012-9550-8] [PMID: 22821546]
[28]
Amant, F.; Moerman, P.; Neven, P.; Timmerman, D.; Van Limbergen, E.; Vergote, I. Endometrial cancer. Lancet, 2005, 366(9484), 491-505.
[http://dx.doi.org/10.1016/S0140-6736(05)67063-8] [PMID: 16084259]
[29]
Opławski, M.; Michalski, M.; Witek, A.; Michalski, B.; Zmarzły, N.; Jęda-Golonka, A.; Styblińska, M.; Gola, J.; Kasprzyk-Żyszczyńska, M.; Mazurek, U.; Plewka, A. Identification of a gene expression profile associated with the regulation of angiogenesis in endometrial cancer. Mol. Med. Rep., 2017, 16(3), 2547-2555.
[http://dx.doi.org/10.3892/mmr.2017.6868] [PMID: 28656251]
[30]
Castel, S.E.; Martienssen, R.A. RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond. Nat. Rev. Genet., 2013, 14(2), 100-112.
[http://dx.doi.org/10.1038/nrg3355] [PMID: 23329111]
[31]
Catalanotto, C.; Cogoni, C.; Zardo, G. MicroRNA in control of gene expression: An overview of nuclear functions. Int. J. Mol. Sci., 2016, 17(10) E1712
[http://dx.doi.org/10.3390/ijms17101712] [PMID: 27754357]
[32]
Matsui, M.; Chu, Y.; Zhang, H.; Gagnon, K.T.; Shaikh, S.; Kuchimanchi, S.; Manoharan, M.; Corey, D.R.; Janowski, B.A. Promoter RNA links transcriptional regulation of inflammatory pathway genes. Nucleic Acids Res., 2013, 41(22), 10086-10109.
[http://dx.doi.org/10.1093/nar/gkt777] [PMID: 23999091]
[33]
Majid, S.; Dar, A.A.; Saini, S.; Yamamura, S.; Hirata, H.; Tanaka, Y.; Deng, G.; Dahiya, R. MicroRNA-205-directed transcriptional activation of tumor suppressor genes in prostate cancer. Cancer, 2010, 116(24), 5637-5649.
[http://dx.doi.org/10.1002/cncr.25488] [PMID: 20737563]
[34]
Liu, M.; Roth, A.; Yu, M.; Morris, R.; Bersani, F.; Rivera, M.N.; Lu, J.; Shioda, T.; Vasudevan, S.; Ramaswamy, S.; Maheswaran, S.; Diederichs, S.; Haber, D.A. The IGF2 intronic miR-483 selectively enhances transcription from IGF2 fetal promoters and enhances tumorigenesis. Genes Dev., 2013, 27(23), 2543-2548.
[http://dx.doi.org/10.1101/gad.224170.113] [PMID: 24298054]
[35]
Grabarek, B.; Wcislo-Dziadecka, D.; Gola, J.; Kruszniewska-Rajs, C.; Brzezinska-Wcislo, L.; Zmarzly, N.; Mazurek, U. Changes in the expression profile of Jak/Stat signaling pathway genes and mirnas regulating their expression under the adalimumab therapy. Curr. Pharm. Biotechnol., 2018, 19(7), 556-565.
[http://dx.doi.org/10.2174/1389201019666180730094046]
[36]
Croce, C.M. Causes and consequences of microRNA dysregulation in cancer. Nat. Rev. Genet., 2009, 10(10), 704-714.
[http://dx.doi.org/10.1038/nrg2634] [PMID: 19763153]
[37]
Mie, Y.; Hirano, Y.; Kowata, K.; Nakamura, A.; Yasunaga, M.; Nakajima, Y.; Komatsu, Y. Function control of anti-microrna oligonucleotides using interstrand cross-linked duplexes. Mol. Ther. Nucleic Acids, 2018, 10, 64-74.
[http://dx.doi.org/10.1016/j.omtn.2017.11.003] [PMID: 29499957]
[38]
Yang, Y.; Jia, Y.; Xiao, Y.; Hao, Y.; Zhang, L.; Chen, X.; He, J.; Zhao, Y.; Qian, Z. Tumor-targeting anti-microrna-155 delivery based on biodegradable poly(ester amine) and hyaluronic acid shielding for lung cancer therapy. ChemPhysChem, 2018, 19(16), 2058-2069.
[http://dx.doi.org/10.1002/cphc.201701375] [PMID: 29488305]
[39]
Passadouro, M.; Faneca, H. Combination of anti-miRNAs oligonucleotides with low amounts of chemotherapeutic agents for pancreatic cancer therapy. Methods Mol. Biol., 2018, 1699, 135-154.
[http://dx.doi.org/10.1007/978-1-4939-7435-1_11] [PMID: 29086375]
[40]
Lv, B.; Cheng, X.; Sharp, F.R.; Ander, B.P.; Liu, D.Z. MicroRNA-122 mimic improves stroke outcomes and indirectly inhibits NOS2 after middle cerebral artery occlusion in rats. Front. Neurosci., 2018, 12, 767.
[http://dx.doi.org/10.3389/fnins.2018.00767] [PMID: 30405345]
[41]
Bonci, D.; Coppola, V.; Musumeci, M.; Addario, A.; Giuffrida, R.; Memeo, L.; D’Urso, L.; Pagliuca, A.; Biffoni, M.; Labbaye, C.; Bartucci, M.; Muto, G.; Peschle, C.; De Maria, R. The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat. Med., 2008, 14(11), 1271-1277.
[http://dx.doi.org/10.1038/nm.1880] [PMID: 18931683]
[42]
Guo, S.T.; Jiang, C.C.; Wang, G.P.; Li, Y.P.; Wang, C.Y.; Guo, X.Y.; Yang, R.H.; Feng, Y.; Wang, F.H.; Tseng, H.Y.; Thorne, R.F.; Jin, L.; Zhang, X.D. MicroRNA-497 targets insulin-like growth factor 1 receptor and has a tumour suppressive role in human colorectal cancer. Oncogene, 2013, 32(15), 1910-1920.
[http://dx.doi.org/10.1038/onc.2012.214] [PMID: 22710713]
[43]
Calin, G.A.; Cimmino, A.; Fabbri, M.; Ferracin, M.; Wojcik, S.E.; Shimizu, M.; Taccioli, C.; Zanesi, N.; Garzon, R.; Aqeilan, R.I.; Alder, H.; Volinia, S.; Rassenti, L.; Liu, X.; Liu, C.G.; Kipps, T.J.; Negrini, M.; Croce, C.M. MiR-15a and miR-16-1 cluster functions in human leukemia. Proc. Natl. Acad. Sci. USA, 2008, 105(13), 5166-5171.
[http://dx.doi.org/10.1073/pnas.0800121105] [PMID: 18362358]
[44]
Fabbri, M.; Garzon, R.; Cimmino, A.; Liu, Z.; Zanesi, N.; Callegari, E.; Liu, S.; Alder, H.; Costinean, S.; Fernandez-Cymering, C.; Volinia, S.; Guler, G.; Morrison, C.D.; Chan, K.K.; Marcucci, G.; Calin, G.A.; Huebner, K.; Croce, C.M. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyl transferases 3A and 3B. Proc. Natl. Acad. Sci. USA, 2007, 104(40), 15805-15810.
[http://dx.doi.org/10.1073/pnas.0707628104] [PMID: 17890317]
[45]
Zmarzły, N.; Wojdas, E.; Skubis, A.; Sikora, S.; Mazurek, U. DNA methylation: Gene expression regulation. Acta Univ. Lodz. Folia Biol. Oecol., 2016, 12(1), 1-10.
[http://dx.doi.org/10.1515/fobio-2016-0001] [PMID: 27641993]
[46]
Gras, C.; Eiz-Vesper, B.; Jaimes, Y.; Immenschuh, S.; Jacobs, R.; Witte, T.; Blasczyk, R.; Figueiredo, C. Secreted semaphorin 5A activates immune effector cells and is a biomarker for rheumatoid arthritis. Arthritis Rheumatol., 2014, 66(6), 1461-1471.
[http://dx.doi.org/10.1002/art.38425] [PMID: 24585544]
[47]
Floss, D.M.; Schröder, J.; Franke, M.; Scheller, J. Insights into IL-23 biology: From structure to function. Cytokine Growth Factor Rev., 2015, 26(5), 569-578.
[http://dx.doi.org/10.1016/j.cytogfr.2015.07.005] [PMID: 26195433]
[48]
Duvallet, E.; Semerano, L.; Assier, E.; Falgarone, G.; Boissier, M.C. Interleukin-23: A key cytokine in inflammatory diseases. Ann. Med., 2011, 43(7), 503-511.
[http://dx.doi.org/10.3109/07853890.2011.577093] [PMID: 21585245]
[49]
Tang, C.; Chen, S.; Qian, H.; Huang, W. Interleukin-23: As a drug target for autoimmune inflammatory diseases. Immunology, 2012, 135(2), 112-124.
[http://dx.doi.org/10.1111/j.1365-2567.2011.03522.x] [PMID: 22044352]
[50]
Lyu, M.; Li, Y.; Hao, Y.; Sun, T.; Liu, W.; Lyu, C.; Fu, R.; Li, H.; Xue, F.; Liu, X.; Zhang, L.; Yang, R. Elevated semaphorin 5A correlated with Th1 polarization in patients with chronic immune thrombocytopenia. Thromb. Res., 2015, 136(5), 859-864.
[http://dx.doi.org/10.1016/j.thromres.2015.07.032] [PMID: 26272304]
[51]
Demirkol, S.; Gomceli, I.; Isbilen, M.; Dayanc, B.E.; Tez, M.; Bostanci, E.B.; Turhan, N.; Akoglu, M.; Ozyerli, E.; Durdu, S.; Konu, O.; Nissan, A.; Gonen, M.; Gure, A.O. A combined ULBP2 and SEMA5A expression signature as a prognostic and predictive biomarker for colon cancer. J. Cancer, 2017, 8(7), 1113-1122.
[http://dx.doi.org/10.7150/jca.17872] [PMID: 28607584]
[52]
Pan, G.; Su, G.; Wang, Y.; Xue, F.; Yang, Y.; Yang, Z.; Zhang, Q.; Liu, T.; Hong, M.; Zheng, J. Effect of Helicobacter pylori on the expression of semaphorin 5A in patients with gastric pre-cancerous lesions and its clinical significance. Int. J. Clin. Exp. Pathol., 2017, 10(2), 1403-1409.
[53]
Xiao, J.B.; Li, X.L.; Liu, L.; Wang, G.; Hao, S.N.; Dong, H.J.; Wang, X.M.; Zhang, Y.F.; Liu, H.D. The association of semaphorin 5A with lymph node metastasis and adverse prognosis in cervical cancer. Cancer Cell Int., 2018, 18, 87.
[http://dx.doi.org/10.1186/s12935-018-0584-1] [PMID: 29977159]
[54]
Lu, T.P.; Tsai, M.H.; Lee, J.M.; Hsu, C.P.; Chen, P.C.; Lin, C.W.; Shih, J.Y.; Yang, P.C.; Hsiao, C.K.; Lai, L.C.; Chuang, E.Y. Identification of a novel biomarker, SEMA5A, for non-small cell lung carcinoma in nonsmoking women. Cancer Epidemiol. Biomarkers Prev., 2010, 19(10), 2590-2597.
[http://dx.doi.org/10.1158/1055-9965.EPI-10-0332] [PMID: 20802022]
[55]
Saxena, S.; Hayashi, Y.; Wu, L.; Awaji, M.; Atri, P.; Varney, M.L.; Purohit, A.; Rachagani, S.; Batra, S.K.; Singh, R.K. Pathological and functional significance of Semaphorin-5A in pancreatic cancer progression and metastasis. Oncotarget, 2017, 9(5), 5931-5943.
[http://dx.doi.org/10.18632/oncotarget.23644] [PMID: 29464045]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy