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Bioinformatic Analysis Divulged Novel Prognostic Circulating MicroRNAs and Their Potential Target Genes in Breast Cancer

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Abstract

Breast cancer (BC) is both an inherited and environmental-based disease which is the leading cause of death among women. Early detection of BC can prevent invasion and metastasis in patients. Currently, researchers endeavor to find non-invasive biological markers from body fluids. Circulating non-coding RNAs such as microRNAs (miRNAs) can potentially be valuable prognostic and detective biomarkers. To identify novel miRNA-based biomarkers, we utilized bioinformatic tools. To reach this goal, the miRNA expression profiles of GSE31309, GSE 44,281, GSE98181, and GSE118782 were analyzed through a limma package of R. Target gene prediction of differentially expressed miRNAs, called differentially expressed miRNAs (DEMs), between samples of healthy individuals and BC patients was implemented through Multimir package of R. Functional enrichment analysis of predicted target genes through Enrich R (online database) revealed that most of the genes are enriched in the mitochondrial outer membrane for cellular component, intrinsic apoptotic signaling regulations for biological processes, transcription co-receptor activity for molecular functions, and dopaminergic synapse pathway. Furthermore, our survival analysis results revealed that miR-29c and mir-361 have the potential to serve as prognostic biomarkers.

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Data Availability

All databases (NCBI GEO, DAVID, Venn diagram) are freely available on the web. The Vesiclepedia database also helped us assess the potential presence of these circulatory miRNAs in serum and cerebrospinal fluid-derived exosomes.

References

  1. Ahmed, F. E. (2007). Role of miRNA in carcinogenesis and biomarker selection: A methodological view. Expert review of molecular diagnostics, 7(5), 569–603.

    Article  CAS  Google Scholar 

  2. Alipour, M. R., Naderi, R., Alihemmati, A., Sheervalilou, R., & Ghiasi, R. (2020). Swimming training attenuates pancreatic apoptosis through miR-34a/Sirtu in1/P53 Axis in high-fat diet and Streptozotocin-induced Type-2 diabetic rats. Journal of Diabetes & Metabolic Disorders, 19(2), 1439–1446.

    Article  CAS  Google Scholar 

  3. Alirol, E., & Martinou, J.-C. (2006). Mitochondria and cancer: Is there a morphological connection? Oncogene, 25(34), 4706–4716.

    Article  CAS  Google Scholar 

  4. Apostolou, P., & Papasotiriou, I. (2017). Current perspectives on CHEK2 mutations in breast cancer. Breast Cancer: Targets and Therapy, 9, 331.

    CAS  Google Scholar 

  5. Bahmanpour, Z., Sheervalilou, R., Choupani, J., Shekari Khaniani, M., Montazeri, V., & Mansoori Derakhshan, S. (2019). A new insight on serum microRNA expression as novel biomarkers in breast cancer patients. Journal of Cellular Physiology, 234(11), 19199–19211.

    Article  CAS  Google Scholar 

  6. Berg, W. A., Blume, J. D., Cormack, J. B., Mendelson, E. B., Lehrer, D., Böhm-Vélez, M., . . . Morton, M. J. (2008). Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. Jama, 299(18), 2151-2163.

  7. Cao, L., Wang, M., Dong, Y., Xu, B., Chen, J., Ding, Y., . . . Zhou, X. (2020). Circular RNA circRNF20 promotes breast cancer tumorigenesis and Warburg effect through miR-487a/HIF-1α/HK2. Cell death & disease, 11(2), 1-10.

  8. Cao, Z.-G., Huang, Y.-N., Yao, L., Liu, Y.-R., Hu, X., Hou, Y.-F., & Shao, Z.-M. (2016). Positive expression of miR-361-5p indicates better prognosis for breast cancer patients. Journal of thoracic disease, 8(7), 1772.

    Article  Google Scholar 

  9. Chandrashekar, D. S., Bashel, B., Balasubramanya, S. A. H., Creighton, C. J., Ponce-Rodriguez, I., Chakravarthi, B. V., & Varambally, S. (2017). UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia, 19(8), 649–658.

    Article  CAS  Google Scholar 

  10. Cheng, G. (2015). Circulating miRNAs: Roles in cancer diagnosis, prognosis and therapy. Advanced drug delivery reviews, 81, 75–93.

    Article  CAS  Google Scholar 

  11. Cheshomi, H., & Matin, M. M. (2019). Exosomes and their importance in metastasis, diagnosis, and therapy of colorectal cancer. Journal of cellular biochemistry, 120(2), 2671–2686.

    Article  CAS  Google Scholar 

  12. Cuk, K., Zucknick, M., Madhavan, D., Schott, S., Golatta, M., Heil, J., . . . Sohn, C. (2013). Plasma microRNA panel for minimally invasive detection of breast cancer. PloS one, 8(10), e76729.

  13. Danza, K., De Summa, S., Pinto, R., Pilato, B., Palumbo, O., Merla, G., . . . Tommasi, S. (2015). MiR-578 and miR-573 as potential players in BRCA-related breast cancer angiogenesis. Oncotarget, 6(1), 471.

  14. Eura, Y., Ishihara, N., Oka, T., & Mihara, K. (2006). Identification of a novel protein that regulates mitochondrial fusion by modulating mitofusin (Mfn) protein function. Journal of cell science, 119(23), 4913–4925.

    Article  CAS  Google Scholar 

  15. Fatima, I., Rahdar, A., Sargazi, S., Barani, M., Hassanisaadi, M., & Thakur, V. K. (2021). Quantum dots: Synthesis, antibody conjugation, and HER2-receptor targeting for breast cancer therapy. Journal of functional biomaterials, 12(4), 75. https://doi.org/10.3390/jfb12040075

    Article  CAS  Google Scholar 

  16. Godet, I., & Gilkes, D. M. (2017). BRCA1 and BRCA2 mutations and treatment strategies for breast cancer. Integrative Cancer Science and Therapeutics, 4, 1.

    Article  Google Scholar 

  17. Gonzalez-Begne, M., Lu, B., Han, X., Hagen, F. K., Hand, A. R., Melvin, J. E., & Yates, J. R., III. (2009). Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). Journal of proteome research, 8(3), 1304–1314.

    Article  CAS  Google Scholar 

  18. Harati-Sadegh, M., Mohammadoo-Khorasani, M., Sargazi, S., Saravani, R., Shahraki, S., & Eskandari, E. (2021). Quantitative assessment of the effects of IL-1ß -511 C>T variant on breast cancer risk: An updated meta-analysis of 3331 cases and 3609 controls. Laboratoriums Medizin, 52(1), 36–46. https://doi.org/10.1093/labmed/lmaa055

    Article  Google Scholar 

  19. Humphries, B. A., Cutter, A. C., Buschhaus, J. M., Chen, Y.-C., Qyli, T., Palagama, D. S., . . . Chiang, B. (2020). Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer. Breast Cancer Research, 22, 1-18.

  20. Iacoviello, L., Bonaccio, M., de Gaetano, G., & Donati, M. B. (2021). Epidemiology of breast cancer, a paradigm of the “common soil” hypothesis. Seminars in Cancer Biology, 72, 4–10. https://doi.org/10.1016/j.semcancer.2020.02.010

    Article  CAS  Google Scholar 

  21. Ingenito, F., Roscigno, G., Affinito, A., Nuzzo, S., Scognamiglio, I., Quintavalle, C., & Condorelli, G. (2019). The role of exo-miRNAs in cancer: A focus on therapeutic and diagnostic applications. International Journal of Molecular Sciences, 20(19), 4687.

    Article  CAS  Google Scholar 

  22. Kahraman, M., Röske, A., Laufer, T., Fehlmann, T., Backes, C., Kern, F., . . . Zabler, C. (2018). MicroRNA in diagnosis and therapy monitoring of early-stage triple-negative breast cancer. Scientific reports, 8(1), 1-11.

  23. Li, W., Yi, J., Zheng, X., Liu, S., Fu, W., Ren, L., . . . Du, G. (2018). miR-29c plays a suppressive role in breast cancer by targeting the TIMP3/STAT1/FOXO1 pathway. Clinical epigenetics, 10(1), 1-14.

  24. Li, Y., Zhang, H., Dong, Y., Fan, Y., Li, Y., Zhao, C., . . . Liu, H. (2017). MiR-146b-5p functions as a suppressor miRNA and prognosis predictor in non-small cell lung cancer. Journal of Cancer, 8(9), 1704.

  25. Lu, L., Ju, F., Zhao, H., & Ma, X. (2015). MicroRNA-134 modulates resistance to doxorubicin in human breast cancer cells by downregulating ABCC1. Biotechnology letters, 37(12), 2387–2394.

    Article  CAS  Google Scholar 

  26. Ma, F., Zhang, L., Ma, L., Zhang, Y., Zhang, J., & Guo, B. (2017). MiR-361-5p inhibits glycolytic metabolism, proliferation and invasion of breast cancer by targeting FGFR1 and MMP-1. Journal of Experimental & Clinical Cancer Research, 36(1), 1–12.

    Article  Google Scholar 

  27. Mariadoss, A. V. A., Vinayagam, R., Senthilkumar, V., Paulpandi, M., Murugan, K., Xu, B., . . . David, E. (2019). Phloretin loaded chitosan nanoparticles augments the pH-dependent mitochondrial-mediated intrinsic apoptosis in human oral cancer cells. International journal of biological macromolecules, 130, 997-1008.

  28. Mathieu, M., Martin-Jaular, L., Lavieu, G., & Théry, C. (2019). Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nature cell biology, 21(1), 9–17.

    Article  CAS  Google Scholar 

  29. Michlewski, G., & Cáceres, J. F. (2019). Post-transcriptional control of miRNA biogenesis. Rna, 25(1), 1–16.

    Article  CAS  Google Scholar 

  30. Mollashahee-Kohkan, F., Saravani, R., Khalili, T., Galavi, H., & Sargazi, S. (2019). Levisticum officinale extract triggers apoptosis and down-regulates ZNF703 gene expression in breast cancer cell lines. Rep Biochem Mol Biol, 8(2), 119–125.

    CAS  Google Scholar 

  31. Mortazavi, S. S., Bahmanpour, Z., Daneshmandpour, Y., Roudbari, F., Sheervalilou, R., Kazeminasab, S., & Emamalizadeh, B. (2021). An updated overview and classification of bioinformatics tools for MicroRNA analysis, which one to choose? Computers in Biology and Medicine, 134, 104544.

    Article  CAS  Google Scholar 

  32. Nygren, M., Tekle, C., Ingebrigtsen, V., Mäkelä, R., Krohn, M., Aure, M., . . . Alsner, J. (2014). Identifying microRNAs regulating B7-H3 in breast cancer: The clinical impact of microRNA-29c. British journal of cancer, 110(8), 2072-2080.

  33. O'Brien, K., Lowry, M. C., Corcoran, C., Martinez, V. G., Daly, M., Rani, S., . . . O'Driscoll, L. (2015). miR-134 in extracellular vesicles reduces triple-negative breast cancer aggression and increases drug sensitivity. Oncotarget, 6(32), 32774.

  34. Pathan, M., Fonseka, P., Chitti, S. V., Kang, T., Sanwlani, R., Van Deun, J., . . . Mathivanan, S. (2019). Vesiclepedia 2019: A compendium of RNA, proteins, lipids and metabolites in extracellular vesicles. Nucleic acids research, 47(D1), D516-D519.

  35. Pecorini, S., Gibellini, L., De Biasi, S., Bianchini, E., Nasi, M., Cossarizza, A., & Pinti, M. (2020). Mitochondria, oxidative stress, cancer, and aging. Geriatric Oncology, 183–204.

  36. Porporato, P. E., Filigheddu, N., Bravo-San Pedro, J. M., Kroemer, G., & Galluzzi, L. (2018). Mitochondrial metabolism and cancer. Cell research, 28(3), 265–280.

    Article  CAS  Google Scholar 

  37. Ru, Y., Kechris, K. J., Tabakoff, B., Hoffman, P., Radcliffe, R. A., Bowler, R., . . . Bemis, L. (2014). The multiMiR R package and database: Integration of microRNA–target interactions along with their disease and drug associations. Nucleic acids research, 42(17), e133-e133.

  38. Salas, A., Yao, Y.-G., Macaulay, V., Vega, A., Carracedo, A., & Bandelt, H.-J. (2005). A critical reassessment of the role of mitochondria in tumorigenesis. PLoS Medicine, 2(11), e296.

    Article  Google Scholar 

  39. Saravani, R., Sargazi, S., Rabbani, M., Rahdar, A., & Taboada, P. (2020). Newly crocin-coated magnetite nanoparticles induce apoptosis and decrease VEGF expression in breast carcinoma cells. Journal of Drug Delivery Science and Technology.https://doi.org/10.1016/j.jddst.2020.101987

  40. Sathipati, S. Y., & Ho, S.-Y. (2018). Identifying a miRNA signature for predicting the stage of breast cancer. Scientific reports, 8(1), 1–11.

    Google Scholar 

  41. Sheervalilou, R., Khamaneh, A. M., Sharifi, A., Nazemiyeh, M., Taghizadieh, A., Ansarin, K., & Zarghami, N. (2017). Using miR-10b, miR-1 and miR-30a expression profiles of bronchoalveolar lavage and sputum for early detection of non-small cell lung cancer. Biomedicine & Pharmacotherapy, 88, 1173–1182.

    Article  CAS  Google Scholar 

  42. Sheervalilou, R., Lotfi, H., Shirvaliloo, M., Shanfi, A., Nazemiyeh, M., & Zarghami, N. (2019). Circulating MiR-10b, MiR-1 and M R-30a expression profiles in lung cancer: Possible correlation with clinico-pathologic characteristics and lung cancer detection. International Journal of Molecular and Cellular Medicine, 8(2), 12.

    Google Scholar 

  43. Sheervalilou, R., Shahraki, O., Hasanifard, L., Shirvaliloo, M., Mehranfar, S., Lotfi, H., . . . Nazarlou, Z. (2020). Electrochemical nano-biosensors as novel approach for the detection of lung cancer-related MicroRNAs. Current Molecular Medicine, 20(1), 13-35.

  44. Si, L., Fu, J., Liu, W., Hayashi, T., Nie, Y., Mizuno, K., . . . Ikejima, T. (2020). Silibinin inhibits migration and invasion of breast cancer MDA-MB-231 cells through induction of mitochondrial fusion. Molecular and cellular biochemistry, 463(1), 189-201.

  45. Singh, V. K., & Sharma, P. K. (2020). Oxidative stress and lifestyle-based changes in breast cancer progression. Current Advances in Breast Cancer Research: A Molecular Approach, 208–235.

  46. Sun, Z., Shi, K., Yang, S., Liu, J., Zhou, Q., Wang, G., . . . Yuan, W. (2018). Effect of exosomal miRNA on cancer biology and clinical applications. Molecular cancer, 17(1), 1-19.

  47. Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 71(3), 209–249. https://doi.org/10.3322/caac.21660

    Article  Google Scholar 

  48. Wanet, A., Arnould, T., Najimi, M., & Renard, P. (2015). Connecting mitochondria, metabolism, and stem cell fate. Stem cells and development, 24(17), 1957–1971.

    Article  CAS  Google Scholar 

  49. Xie, M., Lv, Y., Liu, Z., Zhang, J., Liang, C., Liao, X., . . . Li, Y. (2018). Identification and validation of a four-miRNA (miRNA-21-5p, miRNA-9-5p, miR-149-5p, and miRNA-30b-5p) prognosis signature in clear cell renal cell carcinoma. Cancer Management and Research, 10, 5759.

  50. Xie, X., Huang, Y., Chen, L., & Wang, J. (2018). miR-221 regulates proliferation and apoptosis of ovarian cancer cells by targeting BMF. Oncology letters, 16(5), 6697–6704.

    CAS  Google Scholar 

  51. Yang, M., Soga, T., & Pollard, P. J. (2013). Oncometabolites: Linking altered metabolism with cancer. The Journal of clinical investigation, 123(9), 3652–3658.

    Article  CAS  Google Scholar 

  52. Yousefnia, S., Seyed Forootan, F., Seyed Forootan, S., Nasr Esfahani, M. H., Gure, A. O., & Ghaedi, K. (2020). Mechanistic pathways of malignancy in breast cancer stem cells. Frontiers in Oncology, 10, 452.

    Article  Google Scholar 

  53. Zeng, Y., Wang, K. X., Xu, H., & Hong, Y. (2018). Integrative miRNA analysis identifies hsa-miR-3154, hsa-miR-7-3, and hsa-miR-600 as potential prognostic biomarker for cervical cancer. Journal of cellular biochemistry, 119(2), 1558–1566.

    Article  CAS  Google Scholar 

  54. Zhang, R., Li, Y., Dong, X., Peng, L., & Nie, X. (2014). MiR-363 sensitizes cisplatin-induced apoptosis targeting in Mcl-1 in breast cancer. Medical Oncology, 31(12), 347.

    Article  CAS  Google Scholar 

  55. Zhou, W., Fong, M. Y., Min, Y., Somlo, G., Liu, L., Palomares, M. R., . . . Chin, A. R. (2014). Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer cell, 25(4), 501-515.

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Authors and Affiliations

  1. Cellular and Molecular Research Center, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran

    Babak Pourgholamali

  2. Department of Biology, Faculty of Sciences, Arak University, Arak, Iran

    Behnoush Sohrabi

  3. Department of Microbiology, Falavarjan Branch, Islamic Azad University, Isfahan, Iran

    Mandana Salbi

  4. Nourdanesh Institute, Meymeh, Isfahan, Iran

    Sanaz Akbari

  5. Department of Electronic and Electrical Engineering, Shiraz Azad University, Shiraz, Iran

    Iman Rastan

  6. Azad University Central Tehran Branch Faculty of Basic Sciences, Department of Cellular and Molecular Biology, Tehran, Iran

    Masoud Sayaf

  7. Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq

    Abduladheem Turki Jalil

  8. Medical Laboratory Techniques Department, Al-Farahidi University, Baghdad, Iraq

    Mustafa M. Kadhim

  9. Department of Dentistry, Kut University College, Kut, Wasit, Iraq

    Mustafa M. Kadhim

  10. Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran

    Roghayeh Sheervalilou

  11. Department of Biology, Science and Research Branch Islamic Azad university, Tehran, Iran

    Nazanin Mehrzad

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  1. Babak Pourgholamali
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Pourgholamali, B., Sohrabi, B., Salbi, M. et al. Bioinformatic Analysis Divulged Novel Prognostic Circulating MicroRNAs and Their Potential Target Genes in Breast Cancer. Appl Biochem Biotechnol 195, 283–297 (2023). https://doi.org/10.1007/s12010-022-04151-9

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