Introduction
MicroRNAs are RNA molecules that are small and do not translate into protein by negatively regulating the function of messenger RNA (mRNA). MicroRNAs are involved in cancer development, their expression profiles are useful in the diagnosis of cancer, its progression, and its outcome. There are many small RNAs such as ribosomal RNA, small interfering RNA, small nucleolar RNA, and small transfer RNA. MicroRNA and small interfering RNA are similar biochemically and functionally but differ in origins.
What Are MicroRNAs?
MicroRNAs are small single-stranded RNA molecules, which are noncoding (the RNA molecule, which binds to the 3'UTRs (3' untranslated regions) of mRNA and inhibits translation into protein for cell regulation, whereas coding RNA translates into protein for various components such as an enzyme, signal transductors, or cell structures) and helps in regulating gene expression. These microRNAs bind to target mRNA (which helps in protein synthesis) to negatively regulate their function by preventing translation into proteins by a mechanism. MicroRNA contains 5’-phosphate and 3’-hydroxyl ends and has a length of 19 to 20 nucleotides and is derived from a double-stranded region of RNA that has 60 to 70 nucleotides. Around 940 microRNAs have been identified in the human genome. MiRNAs are classified into two groups; TS‐miRNA and onco‐miRNA.
How Is The Sequence Of Maturation Of MicroRNAs?
The microRNA gene is transcribed (a process of making RNA copy from the DNA segment) into primary microRNA, which undergoes nuclear cleavage into precursor microRNA and further into microRNA duplex in the cytoplasm. The microRNA duplex undergoes unwinding and assembles into an RNA-induced silencing complex (RISC), forming a mature microRNA. This microRNA provides a guide by binding to target mRNA (messenger RNA, which helps in protein synthesis) to negatively regulate their function. The level of complimentary between mature microRNA and mRNA causes cleavage or translation repression in mRNA.
What Is The Role Of MicroRNA In Cancer?
The normal cells undergo genetic changes and lead into pre-malignant states which is the initial stage, then into the progression stage which is invasive and causes metastasis (spreading of cancer in the body). These cancer cells have the ability to proliferate without growth signals, do not respond to inhibitory growth signals, escape apoptosis (programmed cell death), form or stop angiogenesis (formation of new blood vessels), and can spread the tumor. The genes which help in the regulation of cancer cells are:
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Oncogenes: They have chromatin remodelers, growth factors, and their receptors, signal transducers, transcription factors (a protein that controls transcription, in which an RNA copy is made from a segment of DNA), and apoptosis (organized cell death) regulators, overexpression of these can lead to selective growth advantages which can cause tumor development. These oncogenes are activated by alterations in genetics and cause an increase in gene expression and alter the protein structure.
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Tumor Suppressor Genes: These regulate biological processes. loss in their function can cause dysregulation which is associated with cancer.
MicroRNAs play important role in regulating cellular and metabolic pathways, by controlling cell survival, differentiation, and proliferation. The different types are:
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Let-7 miRNAs: Let-7 genes are tumor suppressor genes found in the human genome and are frequently altered or deleted due to cancers. Two targets of Let-7 genes are oncogenes, which are:
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Ras: This delivers signals of growth, proliferation, cell movements, cytoskeleton organization, and survival from cell surface receptors. Cancers of the pancreas, thyroid colon, and lungs contain active Ras mutants
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High Mobility Group AT-hook 2 (HMG2A): Causes alteration in DNA confirmation and influences cell differentiation, proliferation, growth, and survival. HMG2A is found in embryonic tissues, lung cancer, and uterine leiomyomas.
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miR-15 and miR-16: These contain four putative tumor suppressors, which target the anti-apoptotic protein BCL2, which promotes cell survival and is found in various tumors and hematopoietic malignancies.
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miR-21: Its repression causes tumor growth, cell transformation, invasion, and metastasis and is commonly found in human glioblastoma tumors (a type of brain cancer), and cancers of the liver, pancreas, breast, colon, and prostate. miR-21 regulate four genes which are:
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Mapsin.
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Programmed cell death 4 (PDCD4).
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Tropomyosin1 (TPM1).
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Phosphatase and tensin homolog (PTEN).
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miR-17-92: It is a complex cluster and has six mature miRNAs which are miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, and miR-92-1. It is an oncogene and a tumor suppressor. MiR-17-5p and miR-20a of this cluster bind to E2F transcription factors, these factors regulate cell proliferation and apoptosis. miR-17-5p regulates the proto-oncogenic transcriptional activator AIB1 (amplified in breast cancer 1) is a tumor suppressor which regulates growth, proliferation, differentiation, survival, and anchorage-independent growth by inhibiting AIB1 translation. Elevated levels of miR-17-92 miRNAs are found in lung cancer, lymphomas, pancreas, colon, and prostate cancers.
How Is MicroRNAs Profiling Done?
MiRNA profiling is done using a bead-based flow cytometric expression and bead-array profiling, which is highly specific, accurate, and low cost, and other techniques such as quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) can be used. MiRNA signature profiles are used in determining response to drug therapy, treatment efficiency, the prognosis of the disease, race susceptibility of the patient to cancer and metastasis, and help in differentiating between normal and malignant B-cells in chronic lymphatic leukemia and can also be utilized in identifying undifferentiated tumors from their organ of origin. MiRNAs circulate in exosomes of normal and tumor-derived cells, these exomes protect miRNAs from degradation and help in stability. Other theories suggest that they are from lysed cells and that stability is because of binding with DNA, proteins, or lipids. MiRNAs can be extracted from body fluids such as saliva, serum, plasma, and urine.
Conclusion
MiRNA is used as a biomarker for diagnosis and prognosis. The discovery of miRNAs has led to a frame of reference in regulating gene expression. To date up to 940 miRNAs have been identified. MiRNAs are both oncogenes and tumor suppression genes. Dysregulation of miRNAs has been associated with most cancers. MiRNAs are also used as a therapeutic target, their modulation can be done using chemically modified oligonucleotides, which inhibit miRNA target binding since they are smaller than proteins, and they can be delivered in cancer patients. With the ongoing research, miRNA‐based therapeutics can be used along with surgical intervention, radiotherapy, and chemotherapy.
