Doksorubisin ile ilişkili kardiyotoksisitede miR-130a-3p’nin potansiyel hedef genlerinin araştırılması ve tanımlanması için biyoinformatik bir yaklaşım

Year 2021, Volume: 11 Issue: 3, 964 - 974, 15.07.2021

Hamid Ceylan

https://doi.org/10.17714/gumusfenbil.842966

Cited By: 1

Abstract

Doksorubisin (DOX), en etkili kemoterapi ilaçlarından biri olarak kabul edilmekte ve birçok kanser türünü tedavi etmek için kullanılmaktadır. Öte yandan, bu ilacın etkinliği, kardiyotoksisite gibi olumsuz yan etkileri nedeniyle sınırlıdır. Bununla birlikte, DOX kaynaklı kardiyotoksisitenin kesin mekanizması tam olarak anlaşılmamıştır. Bu çalışmada, İlaca bağlı kardiyotoksisitenin moleküler mekanizmasını daha iyi anlamak için kalbe özgü bir miRNA'yı ve kalpteki hedef genlerini belirlemeye odaklanmıştır. Herkese açık veriler, Gene Expression Omnibus (GEO) veri tabanından indirildi ve farklı şekilde ifade edilen genler (DEG'ler), çevrimiçi biyoinformatik aracı iPathwayGuide kullanılarak belirlendi. Sekiz farklı tahmin aracı kullanılarak miR-130a-3p'nin hedef genleri belirlendi. miR-130a-3p hedefleriyle kesişen DEG'ler için gen ontolojisi (GO) ve Kyoto Encyclopedia of Genes and Genomes (KEGG) yolu zenginleştirme analizi yapıldı. Kalp yetmezliği (HF) olan ve HF olmayan gruplar arasında, aynı zamanda miR-130a-3p'nin de hedefi olan toplam 29 DEG tespit edildi. Kesişen genler arasında yer alan SLC8A1'in bozulmuş miyokardiyal fonksiyon ve kardiyotoksisitede şekillenen çok önemli bir gen olabileceğini bulundu. Çalışmanın bulguları, DOX kaynaklı kardiyotoksisitenin teşhisi, tedavisi ve / veya azaltılması için potansiyel hedeflere yeni bilgiler sağlamaktadır.

Keywords

Biyoinformatik analiz, Kardiyotoksisite, Farklı şekilde ifade edilen genler, Doksorubisin, mikroRNA

Supporting Institution

Yok

Project Number

Yok

Thanks

Yok

A bioinformatics approach for exploring and identification of potential target genes of miR-130a-3p in doxorubicin-associated cardiotoxicity

Abstract

Doxorubicin (DOX) is considered one of the most effective chemotherapy drug and is used to treat many types of cancer. On the other hand, the effectiveness of this drug is restricted due to its adverse effects such as cardiotoxicity. However, the exact mechanism of DOX-induced cardiotoxicity has not been fully understood. To better understand the molecular mechanism of DOX-induced cardiotoxicity, this study focused on identifying a heart-specific miRNA and its target genes in the heart. Publicly available data was downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were extracted by using the online bioinformatics tool iPathwayGuide. Using eight different prediction tools, target genes of miR-130a-3p were identified. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for DEGs intersected with miR-130a-3p targets. Among the HF and non-HF groups, a total of 29 DEGs targeted by miR-130a-3p were identified. We found that SLC8A1, which is among the intersecting genes, might be a crucial gene that is shaped in impaired myocardial function and cardiotoxicity. In conclusion, the findings of the study provided new insights into the potential targets for DOX-induced cardiotoxicity diagnosis, treatment, and/or attenuation.

Keywords

Bioinformatics analysis, Cardiotoxicity, Differentially expressed genes, Doxorubicin, microRNA

Project Number

Yok

References

• Agarwal, V., Bell, G. W., Nam, J. W. and Bartel, D. P. (2015). Predicting effective microRNA target sites in mammalian mRNAs. Elife, 4. https://doi.org/10.7554/eLife.05005
• Asli, N. S., Pitulescu, M. E. and Kessel, M. (2008). MicroRNAs in organogenesis and disease. Current Molecular Medicine, 8(8), 698-710. https://doi.org/10.2174/156652408786733739
• Baartscheer, A. (2006). Chronic inhibition of Na(+)/H(+)-exchanger in the heart. Current Vascular Pharmacology, 4(1), 23-29. https://doi.org/10.2174/157016106775203117
• Callis, T. E., Pandya, K., Seok, H. Y., Tang, R. H., Tatsuguchi, M., Huang, Z. P., Chen, J. F., Deng, Z., Gunn, B., Shumate, J., Willis, M. S., Selzman, C. H. and Wang, D. Z. (2009). MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. Journal of Clinical Investigation, 119(9), 2772-2786. https://doi.org/10.1172/JCI36154
• Cappetta, D., De Angelis, A., Sapio, L., Prezioso, L., Illiano, M., Quaini, F., Rossi, F., Berrino, L., Naviglio, S. and Urbanek, K. (2017). Oxidative stress and cellular response to doxorubicin: A common factor in the complex milieu of anthracycline cardiotoxicity. Oxidative Medicine and Cellular Longevity, 2017, 1521020. https://doi.org/10.1155/2017/1521020
• Chang, D., Li, H., Qian, C. and Wang, Y. (2019). DiOHF protects against doxorubicin-induced cardiotoxicity through ERK1 signaling pathway. Front Pharmacol, 10, 1081. https://doi.org/10.3389/fphar.2019.01081
• Chaudhari, U., Nemade, H., Wagh, V., Gaspar, J. A., Ellis, J. K., Srinivasan, S. P., Spitkovski, D., Nguemo, F., Louisse, J., Bremer, S., Hescheler, J., Keun, H. C., Hengstler, J. G. and Sachinidis, A. (2016). Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Archives of Toxicology, 90(11), 2763-2777. https://doi.org/10.1007/s00204-015-1623-5
• Chen, E. Y., Tan, C. M., Kou, Y., Duan, Q., Wang, Z., Meirelles, G. V., Clark, N. R. and Ma'ayan, A. (2013). Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics, 14, 128. https://doi.org/10.1186/1471-2105-14-128
• Chen, Y. and Wang, X. (2020). miRDB: an online database for prediction of functional microRNA targets. Nucleic Acids Research, 48(D1), D127-D131. https://doi.org/10.1093/nar/gkz757
• Clapham, D. E. (2007). Calcium signaling. Cell, 131(6), 1047-1058. https://doi.org/10.1016/j.cell.2007.11.028
• Colpaert, R. M. W. and Calore, M. (2019). MicroRNAs in cardiac diseases. Cells, 8(7). https://doi.org/10.3390/cells8070737
• Deiuliis, J. A. (2016). MicroRNAs as regulators of metabolic disease: pathophysiologic significance and emerging role as biomarkers and therapeutics. International Journal of Obesity, 40(1), 88-101. https://doi.org/10.1038/ijo.2015.170
• Dibb, K. M., Graham, H. K., Venetucci, L. A., Eisner, D. A. and Trafford, A. W. (2007). Analysis of cellular calcium fluxes in cardiac muscle to understand calcium homeostasis in the heart. Cell Calcium, 42(4-5), 503-512. https://doi.org/10.1016/j.ceca.2007.04.002
• Draghici, S., Khatri, P., Tarca, A. L., Amin, K., Done, A., Voichita, C., Georgescu, C. and Romero, R. (2007). A systems biology approach for pathway level analysis. Genome Research, 17(10), 1537-1545. https://doi.org/10.1101/gr.6202607
• Eisner, D. A., Caldwell, J. L., Kistamas, K. and Trafford, A. W. (2017). Calcium and excitation-contraction coupling in the heart. Circulation Research, 121(2), 181-195. https://doi.org/10.1161/CIRCRESAHA.117.310230
• Eisner, D. A., Caldwell, J. L., Trafford, A. W. and Hutchings, D. C. (2020). The control of diastolic calcium in the heart: Basic mechanisms and functional implications. Circulation Research 126(3), 395-412. https://doi.org/10.1161/CIRCRESAHA.119.315891
• Esquela-Kerscher, A. and Slack, F. J. (2006). Oncomirs - microRNAs with a role in cancer. Nature Reviews Cancer, 6(4), 259-269. https://doi.org/10.1038/nrc1840
• Fernandez-Hernando, C. and Suarez, Y. (2018). MicroRNAs in endothelial cell homeostasis and vascular disease. Curr Opin Hematol, 25(3), 227-236. https://doi.org/10.1097/MOH.0000000000000424
• Gennari, A., Sormani, M. P., Pronzato, P., Puntoni, M., Colozza, M., Pfeffer, U. and Bruzzi, P. (2008). HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst, 100(1), 14-20. https://doi.org/10.1093/jnci/djm252
• Gomez, I. G., Nakagawa, N. and Duffield, J. S. (2016). MicroRNAs as novel therapeutic targets to treat kidney injury and fibrosis. Am J Physiol Renal Physiol, 310(10), F931-944. https://doi.org/10.1152/ajprenal.00523.2015
• Han, D., Wang, Y., Wang, Y., Dai, X., Zhou, T., Chen, J., Tao, B., Zhang, J. and Cao, F. (2020). The tumor-suppressive human circular RNA CircITCH Sponges miR-330-5p to ameliorate doxorubicin-induced cardiotoxicity through upregulating SIRT6, survivin, and SERCA2a. Circ Res, 127(4), e108-e125. https://doi.org/10.1161/CIRCRESAHA.119.316061
• Hayashita, Y., Osada, H., Tatematsu, Y., Yamada, H., Yanagisawa, K., Tomida, S., Yatabe, Y., Kawahara, K., Sekido, Y. and Takahashi, T. (2005). A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res, 65(21), 9628-9632. https://doi.org/10.1158/0008-5472.CAN-05-2352
• Heberle, H., Meirelles, G. V., da Silva, F. R., Telles, G. P. and Minghim, R. (2015). InteractiVenn: a web-based tool for the analysis of sets through Venn diagrams. BMC Bioinformatics, 16, 169. https://doi.org/10.1186/s12859-015-0611-3
• Holmgren, G., Sartipy, P., Andersson, C. X., Lindahl, A. and Synnergren, J. (2018). Expression profiling of human pluripotent stem cell-derived cardiomyocytes exposed to doxorubicin-integration and visualization of multi-omics data. Toxicol Sci, 163(1), 182-195. https://doi.org/10.1093/toxsci/kfy012
• Hooning, M. J., Botma, A., Aleman, B. M., Baaijens, M. H., Bartelink, H., Klijn, J. G., Taylor, C. W. and van Leeuwen, F. E. (2007). Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst, 99(5), 365-375. https://doi.org/10.1093/jnci/djk064
• Horie, T., Ono, K., Nishi, H., Nagao, K., Kinoshita, M., Watanabe, S., Kuwabara, Y., Nakashima, Y., Takanabe-Mori, R., Nishi, E., Hasegawa, K., Kita, T. and Kimura, T. (2010). Acute doxorubicin cardiotoxicity is associated with miR-146a-induced inhibition of the neuregulin-ErbB pathway. Cardiovasc Res, 87(4), 656-664. https://doi.org/10.1093/cvr/cvq148
• Hsu, S. D., Lin, F. M., Wu, W. Y., Liang, C., Huang, W. C., Chan, W. L., Tsai, W. T., Chen, G. Z., Lee, C. J., Chiu, C. M., Chien, C. H., Wu, M. C., Huang, C. Y., Tsou, A. P. and Huang, H. D. (2011). miRTarBase: a database curates experimentally validated microRNA-target interactions. Nucleic Acids Res, 39(Database issue), D163-169. https://doi.org/10.1093/nar/gkq1107
• Hu, Y., Xia, W. and Hou, M. (2018). Macrophage migration inhibitory factor serves a pivotal role in the regulation of radiation-induced cardiac senescencethrough rebalancing the microRNA-34a/sirtuin 1 signaling pathway. Int J Mol Med, 42(5), 2849-2858. https://doi.org/10.3892/ijmm.2018.3838
• Huang, J., Zhao, M., Hu, H., Wang, J., Ang, L. and Zheng, L. (2019). MicroRNA-130a reduces drug resistance in breast cancer. Int J Clin Exp Pathol, 12(7), 2699-2705.
• Jing, X., Yang, J., Jiang, L., Chen, J. and Wang, H. (2018). MicroRNA-29b Regulates the mitochondria-dependent apoptotic pathway by targeting bax in doxorubicin cardiotoxicity. Cell Physiol Biochem, 48(2), 692-704. https://doi.org/10.1159/000491896
• Karagkouni, D., Paraskevopoulou, M. D., Chatzopoulos, S., Vlachos, I. S., Tastsoglou, S., Kanellos, I., Papadimitriou, D., Kavakiotis, I., Maniou, S., Skoufos, G., Vergoulis, T., Dalamagas, T. and Hatzigeorgiou, A. G. (2018). DIANA-TarBase v8: a decade-long collection of experimentally supported miRNA-gene interactions. Nucleic Acids Res, 46(D1), D239-D245. https://doi.org/10.1093/nar/gkx1141
• Kim, G. H., Samant, S. A., Earley, J. U. and Svensson, E. C. (2009). Translational control of FOG-2 expression in cardiomyocytes by microRNA-130a. PLoS One, 4(7), e6161. https://doi.org/10.1371/journal.pone.0006161
• Lagos-Quintana, M., Rauhut, R., Yalcin, A., Meyer, J., Lendeckel, W. and Tuschl, T. (2002). Identification of tissue-specific microRNAs from mouse. Curr Biol, 12(9), 735-739. https://doi.org/10.1016/s0960-9822(02)00809-6
• Landstrom, A. P., Dobrev, D. and Wehrens, X. H. T. (2017). Calcium signaling and cardiac arrhythmias. Circ Res, 120(12), 1969-1993. https://doi.org/10.1161/CIRCRESAHA.117.310083
• Li, J., Wan, W., Chen, T., Tong, S., Jiang, X. and Liu, W. (2019). miR-451 Silencing inhibited doxorubicin exposure-induced cardiotoxicity in mice. Biomed Res Int, 2019, 1528278. https://doi.org/10.1155/2019/1528278
• Li, N., Zhou, H. and Tang, Q. (2018). miR-133: A suppressor of cardiac remodeling? Front Pharmacol, 9, 903. https://doi.org/10.3389/fphar.2018.00903
• Li, Q., Qin, M., Tan, Q., Li, T., Gu, Z., Huang, P. and Ren, L. (2020). MicroRNA-129-1-3p protects cardiomyocytes from pirarubicin-induced apoptosis by down-regulating the GRIN2D-mediated Ca(2+) signalling pathway. J Cell Mol Med, 24(3), 2260-2271. https://doi.org/10.1111/jcmm.14908
• Luminari, S., Montanini, A. and Federico, M. (2011). Anthracyclines: a cornerstone in the management of non-Hodgkin's lymphoma. Hematol Rep, 3(3s), e4. https://doi.org/10.4081/hr.2011.s3.e4
• Maragkakis, M., Reczko, M., Simossis, V. A., Alexiou, P., Papadopoulos, G. L., Dalamagas, T., Giannopoulos, G., Goumas, G., Koukis, E., Kourtis, K., Vergoulis, T., Koziris, N., Sellis, T., Tsanakas, P. and Hatzigeorgiou, A. G. (2009). DIANA-microT web server: elucidating microRNA functions through target prediction. Nucleic Acids Res, 37(Web Server issue), W273-276. https://doi.org/10.1093/nar/gkp292
• McCaffrey, T. A., Tziros, C., Lewis, J., Katz, R., Siegel, R., Weglicki, W., Kramer, J., Mak, I. T., Toma, I., Chen, L., Benas, E., Lowitt, A., Rao, S., Witkin, L., Lian, Y., Lai, Y., Yang, Z. and Fu, S. W. (2013). Genomic profiling reveals the potential role of TCL1A and MDR1 deficiency in chemotherapy-induced cardiotoxicity. Int J Biol Sci, 9(4), 350-360. https://doi.org/10.7150/ijbs.6058
• McGowan, J. V., Chung, R., Maulik, A., Piotrowska, I., Walker, J. M. and Yellon, D. M. (2017). Anthracycline chemotherapy and cardiotoxicity. Cardiovasc Drugs Ther, 31(1), 63-75. https://doi.org/10.1007/s10557-016-6711-0
• Melguizo, C., Cabeza, L., Prados, J., Ortiz, R., Caba, O., Rama, A. R., Delgado, A. V. and Arias, J. L. (2015). Enhanced antitumoral activity of doxorubicin against lung cancer cells using biodegradable poly(butylcyanoacrylate) nanoparticles. Drug Des Devel Ther, 9, 6433-6444. https://doi.org/10.2147/DDDT.S92273
• Nielsen, C. B., Shomron, N., Sandberg, R., Hornstein, E., Kitzman, J. and Burge, C. B. (2007). Determinants of targeting by endogenous and exogenous microRNAs and siRNAs. RNA, 13(11), 1894-1910. https://doi.org/10.1261/rna.768207
• Pakravan, G., Foroughmand, A. M., Peymani, M., Ghaedi, K., Hashemi, M. S., Hajjari, M. and Nasr-Esfahani, M. H. (2018). Downregulation of miR-130a, antagonized doxorubicin-induced cardiotoxicity via increasing the PPARgamma expression in mESCs-derived cardiac cells. Cell Death Dis, 9(7), 758. https://doi.org/10.1038/s41419-018-0797-1
• Pecoraro, M., Rodriguez-Sinovas, A., Marzocco, S., Ciccarelli, M., Iaccarino, G., Pinto, A. and Popolo, A. (2017). Cardiotoxic Effects of short-term doxorubicin administration: Involvement of connexin 43 in calcium impairment. Int J Mol Sci, 18(10). https://doi.org/10.3390/ijms18102121
• Pellegrini, L., Sileno, S., D'Agostino, M., Foglio, E., Florio, M. C., Guzzanti, V., Russo, M. A., Limana, F. and Magenta, A. (2020). MicroRNAs in cancer treatment-induced cardiotoxicity. Cancers (Basel), 12(3). https://doi.org/10.3390/cancers12030704
• Sawyer, D. B., Peng, X., Chen, B., Pentassuglia, L. and Lim, C. C. (2010). Mechanisms of anthracycline cardiac injury: can we identify strategies for cardioprotection? Prog Cardiovasc Dis, 53(2), 105-113. https://doi.org/10.1016/j.pcad.2010.06.007
• Songbo, M., Lang, H., Xinyong, C., Bin, X., Ping, Z. and Liang, S. (2019). Oxidative stress injury in doxorubicin-induced cardiotoxicity. Toxicol Lett, 307, 41-48. https://doi.org/10.1016/j.toxlet.2019.02.013
• Thomas, P. D., Campbell, M. J., Kejariwal, A., Mi, H., Karlak, B., Daverman, R., Diemer, K., Muruganujan, A. and Narechania, A. (2003). PANTHER: a library of protein families and subfamilies indexed by function. Genome Res, 13(9), 2129-2141. https://doi.org/10.1101/gr.772403
• Tokar, T., Pastrello, C., Rossos, A. E. M., Abovsky, M., Hauschild, A. C., Tsay, M., Lu, R. and Jurisica, I. (2018). mirDIP 4.1-integrative database of human microRNA target predictions. Nucleic Acids Res, 46(D1), D360-D370. https://doi.org/10.1093/nar/gkx1144
• Volkova, M. and Russell, R., 3rd. (2011). Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr Cardiol Rev, 7(4), 214-220. https://doi.org/10.2174/157340311799960645
• Wallace, K. B. (2007). Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis. Cardiovasc Toxicol, 7(2), 101-107. https://doi.org/10.1007/s12012-007-0008-2
• Yadi, W., Shurui, C., Tong, Z., Suxian, C., Qing, T. and Dongning, H. (2020). Bioinformatic analysis of peripheral blood miRNA of breast cancer patients in relation with anthracycline cardiotoxicity. BMC Cardiovasc Disord, 20(1), 43. https://doi.org/10.1186/s12872-020-01346-y
• Yao, Q., Chen, Y. and Zhou, X. (2019). The roles of microRNAs in epigenetic regulation. Curr Opin Chem Biol, 51, 11-17. https://doi.org/10.1016/j.cbpa.2019.01.024
• Yao, S. (2016). MicroRNA biogenesis and their functions in regulating stem cell potency and differentiation. Biol Proced Online, 18, 8. https://doi.org/10.1186/s12575-016-0037-y
• Ye, J., Zou, M., Li, P. and Liu, H. (2018). MicroRNA regulation of energy metabolism to induce chemoresistance in cancers. Technol Cancer Res Treat, 17, 1533033818805997. https://doi.org/10.1177/1533033818805997
• Zhang, Y., Chen, Y., Zhang, M., Tang, Y., Xie, Y., Huang, X. and Li, Y. (2014). Doxorubicin induces sarcoplasmic reticulum calcium regulation dysfunction via the decrease of SERCA2 and phospholamban expressions in rats. Cell Biochem Biophys, 70(3), 1791-1798. https://doi.org/10.1007/s12013-014-0130-2
• Zhao, L. and Zhang, B. (2017). Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes. Sci Rep, 7, 44735. https://doi.org/10.1038/srep44735
• Zhao, Y., Ransom, J. F., Li, A., Vedantham, V., von Drehle, M., Muth, A. N., Tsuchihashi, T., McManus, M. T., Schwartz, R. J. and Srivastava, D. (2007). Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell, 129(2), 303-317. https://doi.org/10.1016/j.cell.2007.03.030