miRNAs as biomarkers in human diseases

Abstract

RNA interference (RNAi) is one of the primary machineries involved in the regulation of gene expression using small double-stranded RNA (dsRNA) in eukaryotic cells. MicroRNA (miRNA) is a class of small non-coding RNAs, regulating gene expression through canonical and non-canonical ways. Previous studies have shown that miRNA coding sequences make up 1% of the human genome and currently 1917 human miRNAs are displayed in the miRBase database. Expression levels of circulating miRNAs are related to various pathophysiological conditions such as cancer, infectious conditions, cardiovascular diseases, neurodegenerative diseases, and many more. Therefore, it is important to identify, detect and analyse miRNAs by using in silico and experimental analyses. In this review, after a brief description, we discuss the use of miRNAs for diagnosis and prognosis as biomarkers and biosensors in addition to miRNA-based therapies.

Keywords

• Biomarker
• Biosensor
• Gene Expression Regulation
• Small Non-Coding RNAs

References

1. Aghili, Z., Nasirizadeh, N., Divsalar, A., Shoeibi, S., Yaghmaei, P. 2018. A highly sensitive miR-195 nano biosensor for early detection of Parkinson’s disease. Artificial Cells, Nanomedicine, and Biotechnology, 46(sup1), 32-40.
2. Almeida, R., Allshire, R. C. 2005. RNA silencing and genome regulation. Trends in Cell Biology, 15(5), 251–258.
3. Altschul, S. F., Gish, W., Miller, W., Myers, E. W. et al. 1990. Basic local alignment search tool. Journal of Molecular Biology, 215(3), 403-410.
4. Axtell, M. J., Bowman, J. L. 2008. Evolution of plant microRNAs and their targets. Trends in plant science, 13(7), 343-349.
5. Bartel, D. P. 2004. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell, 116(2), 281-297.
6. Bartel, D. P., Chen, C. Z. 2004. Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nature Reviews Genetics, 5(5), 396-400.
7. Bartlett, B., Gao, Z., Schukking, M., Menor, M., Khadka, V. S. et al. 2021. The miRNA profile of inflammatory colorectal tumors identify TGF-β as a companion target for checkpoint blockade immunotherapy. Frontiers in Cell and Developmental Biology, 9, 754507.
8. Berner, K., Hirschfeld, M., Weiß, D., Rücker, G., Asberger, J. et al. 2021. Evaluation of circulating microRNAs as non-invasive biomarkers in the diagnosis of ovarian cancer: A case-control study. Archives Of Gynecology and Obstetrics, 10.1007/s00404-021-06287-1.

9. Bhardwaj, A., Arora, S., K Prajapati, V., Singh, S., P Singh, A. 2013. Cancer “stemness”-regulating microRNAs: role, mechanisms and therapeutic potential. Current drug targets, 14(10), 1175-1184.
10. Biswas, S., Haleyurgirisetty, M., Lee, S., Hewlett, I., Devadas, K. 2019. Development and validation of plasma miRNA biomarker signature panel for the detection of early HIV-1 infection. EBioMedicine, 43, 307-316.
11. Brüggenwirth, I. M., Martins, P. N. 2020. RNA interference therapeutics in organ transplantation: The dawn of a new era. American Journal of Transplantation, 20(4), 931-941. Castel, S. E., Martienssen, R. A. 2013. RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond. Nature Reviews Genetics, 14(2), 100-112.
12. Chen, C., Ridzon, D. A., Broomer, A. J., Zhou, Z., Lee, D. H. et al. 2005. Real-time quantification of microRNAs by stem–loop RT–PCR. Nucleic Acids Research, 33(20), e179-e179.
13. Chetta, M., Di Pietro, L., Bukvic, N., Lattanzi, W. 2020. Rising roles of small noncoding RNAs in cotranscriptional regulation: In silico study of miRNA and piRNA regulatory network in humans. Genes, 11(5), 482.
14. Chevillet, J. R., Lee, I., Briggs, H. A., He, Y., Wang, K. 2014. Issues and prospects of microRNA-based biomarkers in blood and other body fluids. Molecules, 19(5), 6080-6105.
15. Coban, N., Pirim, D., Erkan, A. F., Dogan, B., Ekici, B. 2020. Hsa-miR-584-5p as a novel candidate biomarker in Turkish men with severe coronary artery disease. Molecular Biology Reports, 47(2), 1361–1369.
16. Conesa, A., Götz, S. 2008. Blast2GO: a comprehensive suite for functional analysis in plant genomics. International Journal of Plant Genomics, 10.1155/2008/619832.
17. Covarrubias, A. A., Reyes, J. L. 2010. Post‐transcriptional gene regulation of salinity and drought responses by plant microRNAs. Plant, Cell Environment, 33(4), 481-489.
18. de Rie, D., Abugessaisa, I., Alam, T., Arner, E., Arner, P. et al. 2017. An integrated expression atlas of miRNAs and their promoters in human and mouse. Nature Biotechnology, 35(9), 872-878.
19. Deng, Y., Wang, C. C., Choy, K. W., Du, Q., Chen, J.et al. 2014. Therapeutic potentials of gene silencing by RNA interference: principles, challenges, and new strategies. Gene, 538(2), 217-227.
20. Duy, J., Koehler, J. W., Honko, A. N., Schoepp, R. J., Wauquier, N. et al. 2016. Circulating microRNA profiles of Ebola virus infection. Scientific Reports, 6(1), 1-13.
21. El-Kafrawy, S. A., Sohrab, S. S., Mirza, Z., Hassan, A. M., Alsaqaf, F. et al. 2021. In vitro inhibitory analysis of rationally designed siRNAs against MERS-CoV replication in Huh7 Cells. Molecules, 26(9), 2610.
22. Fang, C., Li, X. P., Chen, Y. X., Wu, N. Y., Yin, J. Y. et al. 2018. Functional miRNA variants affect lung cancer susceptibility and platinum-based chemotherapy response. Journal of Thoracic Disease, 10(6), 3329.
23. Friedman, R. C., Farh, K. K. H., Burge, C. B., Bartel, D. P. 2009. Most mammalian mRNAs are conserved targets of microRNAs. Genome Research, 19(1), 92-105.
24. Garcia, A., Dunoyer-Geindre, S., Nolli, S., Reny, J. L., Fontana, P. 2021. An ex vivo and in silico study providing insights into the interplay of circulating miRNAs level, platelet reactivity and thrombin generation: looking beyond traditional pharmacogenetics. Journal of Personalized Medicine, 11(5), 323.
25. Hayder, H., O’Brien, J., Nadeem, U., Peng, C. 2018. MicroRNAs: crucial regulators of placental development. Reproduction, 155(6), R259-R271.
26. He, H., Song, F., Gao, Q., Lu, Z., Yuan, Y. et al. 2021. The APEX1/miRNA-27a-5p axis plays key roles in progression, metastasis and targeted chemotherapy of gastric cancer. International Journal of Pharmaceutics, 599, 120446.
27. He, M., Lin, Y., Xu, Y. 2019. Identification of prognostic biomarkers in colorectal cancer using a long non coding RNA mediated competitive endogenous RNA network. Oncology Letters, 17(3), 2687-2694.
28. Helwak, A., Kudla, G., Dudnakova, T., Tollervey, D. 2013. Mapping the human miRNA interactome by CLASH reveals frequent noncanonical binding. Cell, 153(3), 654-665.
29. Hong, L. Z., Zhou, L., Zou, R., Khoo, C. M., San Chew, A. L. et al. 2021. Systematic evaluation of multiple qPCR platforms, NanoString and miRNA-Seq for microRNA biomarker discovery in human biofluids. Scientific Reports, 11(1), 1-11.
30. Jian, C., Han, R., Chi, Q., Wang, S., Ma, M. et al. 2017. Virus-based microRNA silencing and overexpressing in common wheat (Triticum aestivum L.). Frontiers in Plant Science, 8, 500. Jonas, S., Izaurralde, E. 2015. Towards a molecular understanding of microRNA-mediated gene silencing. Nature Reviews Genetics, 16(7), 421-433.
31. Kim, Y. K., Kim, V. N. 2007. Processing of intronic microRNAs. The EMBO Journal, 26(3), 775-783.
32. Kloosterman, W. P., Wienholds, E., de Bruijn, E., Kauppinen, S., Plasterk, R. H. 2006. In situ detection of miRNAs in animal embryos using LNA-modified oligonucleotide probes. Nature Methods, 3(1), 27-29.
33. Kozomara, A., Birgaoanu, M., Griffiths-Jones, S. 2019. miRBase: from microRNA Sequences to Function. Nucleic Acids Research, 47, D155-D162.
34. Krol, J., Loedige, I., Filipowicz, W. 2010. The widespread regulation of microRNA biogenesis, function, and decay. Nature Reviews Genetics, 11(9), 597-610.
35. Kruger, J. and Rehmsmeier, M. 2006. RNAhybrid: microRNA target prediction easy, fast and flexible. Nucleic Acids Research, 34, 451-454.
36. Lee, R. C., Feinbaum, R. L., Ambros, V. 1993. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell, 75(5), 843-854.
37. Lee, Y., Kim, M., Han, J., Yeom, K. H., Lee, S.et al. 2004. MicroRNA genes are transcribed by RNA polymerase II. The EMBO Journal, 23(20), 4051-4060.
38. Liu, H., Bian, Q. Z., Zhang, W., Cui, H. B. 2022. Circulating microRNA 103a 3p could be a diagnostic and prognostic biomarker for breast cancer. Oncology Letters, 23(1), 1-9.
39. Liu, Q., Paroo, Z. 2010. Biochemical principles of small RNA pathways. Annual Review of Biochemistry, 79, 295-319.
40. Lorenz, R., Bernhart, S. H., Zu Siederdissen, C. H., Tafer, H., Flamm, C.et al. 2011. ViennaRNA Package 2.0. Algorithms for Molecular Biology, 6(1), 26.
41. Mardis, E.R. 2000. Next-generation DNA sequencing methods. Annual Review of Genomics and Human Genetics. 9, 387-402.
42. Movahedi, A., Zhang, J., Sun, W., Kadkhodaei, S., Mohammadi, K. et al. 2018. Plant small RNAs: definition, classification, and response against stresses. Biologia, 73(3), 285-294.
43. Nik Mohamed Kamal, N. Shahidan, W. N. S. 2020. Non-exosomal and exosomal circulatory microRNAs: Which are more valid as biomarkers?. Frontiers in Pharmacolgy, 10, 1500.
44. O’Brien, J., Hayder, H., Zayed, Y., Peng, C. 2018. Overview of MicroRNA biogenesis, mechanisms of actions, and circulation. Front Endocrinol (Lausanne) 9: 402.
45. Ouyang, X., Jiang, X., Gu, D., Zhang, Y., Kong, S. K. et al. 2016. Dysregulated serum miRNA profile and promising biomarkers in dengue-infected patients. International Journal of Medical Sciences, 13(3), 195.
46. Peterson, S. M., Thompson, J. A., Ufkin, M. L., Sathyanarayana, P., Liaw, L. et al. 2014. Common features of microRNA target prediction tools. Frontiers in Genetics, 5, 23.
47. Rana, N. K., Srivastava, N., Koch, B. 2021. Identification of the key miRNA; hsa-miR-1269a targeting TP53, Caspase-9 and FOXO3a in breast cancer cells under hypoxia by integrated bioinformatics analysis. Gene Reports, 25, 101408.
48. Reinhart, B. J., Slack, F. J., Basson, M., Pasquinelli, A. E., Bettinger, J. C. et al. 2000. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature, 403(6772), 901-906.
49. Reinhart, B. J., Weinstein, E. G., Rhoades, M. W., Bartel, B., Bartel, D. P. 2002. MicroRNAs in plants. Genes Development, 16(13), 1616-1626.
50. Sempere, L. F., Freemantle, S., Pitha-Rowe, I., Moss, E., Dmitrovsky, E. et al. 2004. Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biology, 5(3), 1-11.
51. Song, S., Lee, J. U., Jeon, M. J., Kim, S., Sim, S. J. 2021. Detection of multiplex exosomal miRNAs for clinically accurate diagnosis of Alzheimer’s disease using label-free plasmonic biosensor based on DNA-Assembled advanced plasmonic architecture. Biosensors and Bioelectronics, 113864.
52. Stepien, A., Knop, K., Dolata, J., Taube, M., Bajczyk, M. et al. 2017. Posttranscriptional coordination of splicing and miRNA biogenesis in plants. Wiley Interdisciplinary Reviews. RNA, 8(3), 10.1002/wrna.1403.
53. Sun, Y., Yang, B., Lin, M., Yu, H., Chen, H. et al. 2019. Identification of serum miR-30a-5p as a diagnostic and prognostic biomarker in colorectal cancer. Cancer Biomarkers, 24(3), 299-305.
54. Thomson, M., Parker, J., Perou, C. M., Hammond, S. M. 2004. A custom microarray platform was analyzed of miRNA gene expression. Nature Methods, 1, 47-53.
55. Tribolet, L., Kerr, E., Cowled, C., Bean, A. G., Stewart, C. R. et al. 2020. MicroRNA biomarkers for infectious diseases: From basic research to biosensing. Frontiers in Microbiology, 11, 1197.
56. Válóczi, A., Hornyik, C., Varga, N., Burgyán, J., Kauppinen, S. et al. 2004. Sensitive and specific detection of microRNAs by northern blot analysis using LNA-modified oligonucleotide probes. Nucleic Acids Research, 32(22), e175-e175.
57. Wang, J., Chen, J., Chang, P., LeBlanc, A., Li, D., Abbruzzesse, J. L. et al. 2009. MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients as novel blood-based biomarkers of disease. Cancer Prevention Research, 2(9), 807-813.
58. Wang, J., Paris, P. L., Chen, J., Ngo, V., Yao, H. et al. 2015. Next generation sequencing of pancreatic cyst fluid microRNAs from low grade-benign and high grade-invasive lesions. Cancer Letters, 356(2), 404-409.
59. Wang, J., Raimondo, M., Guha, S., Chen, J., Diao, L. et al. 2014. Circulating microRNAs in pancreatic juice as candidate biomarkers of pancreatic cancer. Journal of Cancer, 5(8), 696.
60. Wittmann, J., Jäck, H. M. 2010. New surprises from the deep—the family of small regulatory RNAs increases. The Scientific World Journal, 10, 1239-1243.
61. Xin, Y., Huang, M., Guo, W. W., Huang, Q., Zhang, L. Z. et al. 2017. Nano-based delivery of RNAi in cancer therapy. Molecular Cancer, 16(1), 134.
62. Zeng, D., Wang, Z., Meng, Z., Wang, P., San, L. et al. 2017. DNA tetrahedral nanostructure-based electrochemical miRNA biosensor for simultaneous detection of multiple miRNAs in pancreatic carcinoma. ACS applied materials interfaces, 9(28), 24118-24125.panel for the detection of early HIV-1 infection. EBioMedicine, 43, 307-316.
63. Zhang, M., Shi, Y., Zhang, Y., Wang, Y., Alotaibi. et al. 2020. miRNA-5119 regulates immune checkpoints in dendritic cells to enhance breast cancer immunotherapy. Cancer Immunology, Immunotherapy, 69(6), 951-967.
64. Zhang, Y., Teng, Y., Xiao, W., Xu, B., Zhao, Y. et al. 2020. Identifying cleaved and noncleaved targets of small interfering RNAs and microRNAs in mammalian cells by SpyCLIP. Molecular Therapy-Nucleic Acids, 22, 900-909.
65. Zhang, Z., Dong, Y., Hua, J., Xue, H., Hu, J. et al. 2019. A five-miRNA signature predicts survival in gastric cancer using bioinformatics analysis. Gene, 699, 125-134.