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MicroRNA Biogenesis - Its Function In Promoting Tumor Angiogenesis

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MicroRNAs have essential roles in various biological processes, including differentiation, proliferation, apoptosis, and development in health and illness.

Their dysregulation has a role in tumor formation and evolution.

MicroRNA biogenesis is carefully regulated in place and time, including microRNA transcription, processing by Drosha and Dicer, transportation, RISC-based bidding, and microRNA decay.

MicroRNAs are evolutionarily conserved non-protein-coding regulatory genes that partially complement one or more messenger RNA (mRNA) molecules (target mRNAs).

MicroRNAs have been discovered in eukaryotic species, viruses, and prokaryotic cells.

COPYRIGHT_WI: Published on https://washingtonindependent.com/ebv/microrna-biogenesis/ by Karan Emery on 2022-08-20T23:35:20.319Z

The angiogenic switch is critical in tumor development.

Tumor cells, endothelial cells, and microenvironmental cells generate microRNAs that influence tumor angiogenesis by functioning as pro-angiomiR or anti-angiomiR.

They control the expression of homologous target-gene transcripts at the transcriptional and post-transcriptional levels via an RNA interference mechanism (RNAi).

They may promote down-and-up gene expression through various methods in the cytoplasm and nucleus, where they have been discovered.

What is microRNA (miRNA)?

What Is MicroRNA?

The preponderance of evidence suggests that post-transcriptional gene silencing by microRNA occurs in the cytoplasm and P-bodies.

However, newly identified microRNA and argonaute proteins in human cell nuclei have been demonstrated to suppress nuclear target RNA gene expression.

MiRISC may be able to assemble and be imported into the nuclease. A Caenorhabditis elegans research discovered an argonaute protein called NRDE-3 (nuclear RNAi defective-3), which imports siRNA to the nucleus.

Humans may contain transporter proteins that perform a similar function.

The role of nuclear miRISC is unknown. The finding establishes nuclear non-coding RNA as a novel class of microRNA targets.

MicroRNA may regulate gene transcription, restrict RNA export, or influence target mRNA splicing in the nucleus.

Perhaps nuclear microRNA drives DNA methylation in collaboration with argonaute proteins.

MicroRNA might also be localized in the nucleus for modification.

The nuclear A-to-I editing of microRNA by adenosine deaminase that acts on RNA (ADAR) has been linked to microRNA processing regulation.

The extent of microRNA silencing is unknown, as is the interaction between distinct silencing mechanisms.

Although the overall function of microRNAs is understood, the molecular intricacies of microRNA synthesis and gene silencing remain unknown.

This new and exciting discipline of molecular biology is advancing, with far-reaching ramifications in medicine.

Although the biological role of discovered microRNAs is unclear, examining their expression patterns gives insight into their regulation and function.

Such findings suggest that microRNA expression patterns are changed in particular tumors, hinting that microRNA may play a role in developing cancer and other disorders.

Even though we know so little about these chemicals, basic expression profiling is proven to be therapeutically valuable in cancer diagnosis, progression, and prognosis.

MicroRNA Function

Post-transcriptional gene silencing by microRNA occurs in the cytoplasm and P-bodies.

However, newly identified microRNA and argonaute proteins in human cell nuclei have been demonstrated to suppress nuclear target RNA gene expression.

MicroRISC may be able to assemble and be imported into the nuclease.

Humans may contain transporter proteins that perform a similar function.

The role of nuclear miRISC is unknown. The finding establishes nuclear non-coding RNA as a novel class of microRNA targets.

MicroRNA may regulate gene transcription, restrict RNA export, or influence target mRNA splicing in the nucleus.

Perhaps nuclear microRNA drives DNA methylation in collaboration with argonaute proteins. MicroRNA might also be localized in the nucleus for modification.

The nuclear A-to-I editing of microRNA by adenosine deaminase that acts on RNA (ADAR) has been linked to microRNA processing regulation.

The extent of microRNA silencing is unknown, as is the interaction between distinct silencing mechanisms.

Visual description of DNA strands.
Visual description of DNA strands.

MicroRNA Function In Gene Expression

MicroRNAs are short non-coding RNAs that influence gene expression post-transcriptionally.

They typically attach to their target mRNAs' 3'-UTR (untranslated region) and suppress protein synthesis by destabilizing the mRNA and silencing translation.

Although the precise mechanism of microRNA-mediated translational repression remains unknown, new studies from our group reveal that the stage of translation blocked by microRNAs depends on the promoter utilized to transcribe the target mRNA.

So, if a specific microRNA is underexpressed, the protein it usually regulates may be overexpressed; if the microRNA is overexpressed, the protein it normally regulates will be underexpressed.

What Is MicroRNA Biogenesis?

MicroRNA biogenesis begins with DNA sequences known as microRNA genes or clusters of genes that are solely transcripted as microRNA molecules or collectively as polycistronic transcripts.

MicroRNAs may also be found in an intron or untranslated region (UTR) of a protein-coding gene.

There are two types of biogenesis pathways: canonical and non-canonical.

The MicroRNA Biogenesis Canonical Pathway

In traditional biogenesis, RNA polymerase III transcribes primary microRNAs from their genes.

The microprocessor complex subsequently converts them into precursor microRNAs (pre-microRNAs).

Argonaute RISC Catalytic Component 2 is one of the proteins found in this complex.

RISC with a loaded microRNA (miRISC) inhibits numerous phases of protein synthesis while also influencing mRNA target stability.

It has been shown that the minimum miRISC complex exists in mammalian cell nuclei, where it is 20 times smaller.

It is made up of only Ago2 and microRNA, and it is loaded in the cytoplasm before being imported into the nucleus by IPC8.

MicroRNAs change chromatin structure in the nucleus, govern alternative splicing and regulate themselves.

Transcriptional gene activation (TGA) may also be mediated by microRNA. A sequence of post-translational modifications (PTMs) influencing the microRNA processing machine may modulate microRNA levels and activity.

Changes in microRNA biogenesis may both promote and support cancer development.

Cancer is aided by altered expression levels of microRNA processing machinery components such as Drosha, DGCR8, and Dicer.

Tumors like prostate, breast, ovarian, and bladder cancer grow and stay alive when XPO5 levels rise.

Functions Of Non-Canonical MicroRNAs

In addition to the conventional route, MicroRNAs may be processed from unanticipated non-coding RNAs by methods that vary depending on cell type and cellular state.

MicroRtron-derived pri-microRNAs match the complete intronic sequence of the mRNA-encoding genes in which they are found.

Dicer does not digest pre-miR-451 because its stem-loop structure is too short.

This microRNA is implicated in the development and progression of various malignancies. The significance of non-canonical microRNAs in cancer formation is unknown.

They may influence mRNA stability by binding to it directly, limiting protein translation, or cleaving a partly complementary target site.

The miRtron miR-6778-5p, generated from SHMT1 intron 5 (coding for cytoplasmic serine hydroxymethyltransferase), is a key regulator of cancer stem cell stemness in gastric cancer cells.

Increased nuclear SRSF1 levels are associated with hsa-miR-1229-3p expression. In human breast cancer cell lines, snoRNA-93 was an invasion promoter.

Affect Of PARylation Modification On MicroRNA Function In Tumors

A macromolecular polymer called poly-ADP-ribose (pADPr) is added to specific proteins as a post-translational modification.

pADPr is a critical regulator of microRNA PTMs in the cytoplasm and, as a result, mRNA expression levels.

Increased PARylation inhibits microRNA repression and microRNA-directed cleavage. Protein paradylation during viral infection alleviates interferon-stimulated gene regulation by the miR-17/93 family.

This suggests that cells react to viral infection by decreasing the activity of the microRNA pathway.

PARP13 anticancer activity has also been discovered in Hepatitis B virus-related liver cancer and leukemia.

MicroRNA In Tumors

Tumors form due to progressive DNA changes that enable tumor cells to grow uncontrolled.

MicroRNAs have essential roles in various biological processes, including differentiation, proliferation, and apoptosis.

MicroRNA activity increases in Acute Myeloid Leukemia (AML) patients with myeloid/lymphoid leukemia gene (or mixed-lineage leukemia, MLL) rearrangement.

The significant change of microRNAs in malignancies is abnormal gene expression caused by amplification or deletion of specific genomic regions.

Transcription factors, including p53, c-Myc, nuclear receptors, and RAS, regulate microRNA production and are often linked to cancer.

Oncogenic miR-146b-5p inhibits microRNA production by targeting and suppressing Dicer expression.

Dysregulation of pre-microRNA export, Dicer, and Ago2 are all involved.

Tumor cell proliferation, migration, invasion, and EMT are all aided by Dicer deletion and down-expression.

MiR-744 increases Cyclin B1 transcription by recruiting RNA polymerase II and trimethylating histone-3 at lysine-4 in the promoter region.

In the nucleus of HCT116 colon cancer cells, miR-10a works as a transcriptional repressor of Hoxd4.

MicroRNAs are molecules that communicate between cells and may travel large distances to impact destination cells.

During cellular events such as secretion, apoptosis, inflammation, and necrosis, circulating microRNAs may be released from all cell types as complexes coupled with Argonaute proteins.

MicroRNAs may function as oncogenes or tumor suppressors in malignancies.

The same microRNA may engage in many pathways, each with a specific impact on cell survival, growth, and proliferation.

Pre-microRNA levels were discovered to be changed in many kinds of cancers but not active molecules.

MicroRNA In Angiogenesis

Angiogenesis is the process of forming new blood vessels. In malignancies, many factors may contribute to creating a new vascular network.

The continual production of pro-angiogenic factors hampers blood vessel development.

These characteristics of tumor blood vessels contribute to and perpetuate a hypoxic microenvironment.

It is feasible to differentiate four microRNAs' action modes on tumor angiogenesis.

In the first instance, changes in tumor cells impact the phenotypes of ECs through altering the microenvironment or intercellular interaction.

Second, genetic and epigenetic modifications in ECs influence the cell's phenotypes.

In a paracrine manner, tumor cell-derived microRNAs influence the production of pro or anti-angiogenic molecules.

MicroRNA In Lymphoma

Lymphoma is a malignancy that starts in immune system cells called lymphocytes-T and B. Non-Hodgkin Lymphoma (NHL) and Hodgkin Lymphoma (HL) are the two primary kinds of lymphoma (HL).

NHL may begin in any lymph node in the body, but HL generally starts in the upper region of the body.

In stem and progenitor cells, microRNAs govern cell fate and lineage commitment.

MicroRNA dysregulation has been discovered in solid tumors as well as hematologic cancers.

When compared to healthy blood and pediatric leukemia patients, miR155 was 100-fold higher in children with Burkitt lymphoma. miR-155 affects the functioning of both B and T lymphocytes.

Because of reduced quantities of immunoglobulins, tumor necrosis factor (TNF), and lymphotoxin, its loss results in immunodeficiency.

MicroRagen Therapeutics, a biopharmaceutical business, is developing MRG-106, a locked nucleic acid-modified oligonucleotide inhibitor.

This medication may de-repress cobomarsen in individuals with mycosis fungoides cutaneous T-cell lymphoma.

The miR-17-92 polycistronic cluster, which encodes six microRNAs, is implicated in immune cell development, lymphoma, and angiogenesis.

The NPM-ALK/STAT3-miR-135b axis shifts ALCL cell identity to a Th17 immunophenotype (pro-inflammatory cells) by downregulating GATA3 and STAT6.

Increased neoangiogenesis was seen in p53-null colonocytes co-expressing K-RAS and c-Myc, which was connected with the downregulation of anti-angiogenic thrombospondin-1 (Tsp1) through miRs.

MicroRNA biogenesis, functions and role in diseases : Molecular Microbiology Tutorials

People Also Ask

How Are MicroRNAs Synthesized?

RNA polymerases II and III transcribe microRNAs, producing precursors that undergo a sequence of cleavage events to create mature microRNA.

The traditional biogenesis process comprises two cleavage events, one nuclear and one cytoplasmic.

Where Do MicroRNAs Originate?

MicroRNAs are created by the random construction of hairpins in "non-coding" parts of DNA (i.e., introns or intergene regions).

Still, they may also be made by duplicating and modifying existing microRNAs.

Where Is MicroRNA Formed?

MicroRNAs are generated in animals in two phases from primordial microRNAs (pri-microRNAs) by the action of two RNase III-type proteins: Drosha resides in the nucleus, whereas Dicer resides in the cytoplasm.

Conclusion

The human genome contains about 200,000 mRNAs and roughly 2,600 mature microRNAs.

MicroRNAs may target numerous mRNAs, impacting different biochemical pathways, but mRNAs can also attach to multiple microRNAs, either concurrently or in a context-dependent fashion.

According to computational studies, microRNAs influence around 30% of human protein-coding genes.

Each stage of microRNA biogenesis is meticulously regulated.

As a result, even minor disruptions in microRNA biogenesis and gene expression control might result in cancer.

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About The Authors

Karan Emery

Karan Emery - I'm a research scientist interested in learning more about how neural activity influences and shapes human behavior. Project design and management, data analysis and interpretation, and the creation and implementation of testing tools are among my specialties. I enjoy coming up with new ideas and coming up with practical solutions to issues that are widely applicable. My colleagues would describe me as a driven, resourceful individual who maintains a positive, proactive attitude when faced with adversity. Currently, I’m seeking opportunities that will allow me to develop and promote technologies that benefit human health. Specific fields of interest include data analytics, biotechnology, and pharmaceuticals.

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