miRNAs: Key Regulators in Cancer Biology

The Role of miRNA in Cancer Regulation

MicroRNAs (miRNAs) are small, non-coding RNA molecules that significantly impact gene expression regulation. Their involvement in cancer is a critical research area because these molecules can influence various cancers' development and progression.

Understanding miRNAs

miRNAs are produced from primary miRNA transcripts (pri-miRNAs) through a processing series. These mature miRNAs, about 22 nucleotides long, are integrated into the RNA-induced silencing complex (RISC). Within RISC, miRNAs guide the complex to target messenger RNAs (mRNAs) by matching complementary sequences. This matching results in mRNA degradation or translation inhibition. This regulatory mechanism allows miRNAs to control genes involved in key cellular processes.

The biogenesis and function of miRNA processing. The maturation of miRNAs includes the production of primary miRNA transcripts (pri-miRNA) by RNA polymerase II or III and cleavage of pri-miRNA in the nucleus by the microprocessor complex Drosha-DGCR8 (Pasha). The resulting precursor hairpin, pre-miRNA, is exported from the nucleus via exportin-5-rang-gtp is exported from the nucleus. In the cytoplasm, the functional strand of the mature miRNA is loaded with Argonaute (Ago2) protein into the RNA-induced silencing complex (RISC), where it directs RISC to silence the target mRNA by mRNA cleavage, translational repression or deadenylation, while the passenger strand is degraded

miRNAs in Cancer

Cancer is characterized by abnormal cell growth and division, often caused by genetic and epigenetic changes. miRNAs can function as tumor suppressors or oncogenes (oncomiRs) depending on the genes they regulate.

Tumor Suppressor miRNAs

Tumor suppressor miRNAs typically decrease the activity of genes that promote cell proliferation and survival. For example, miR-34a targets mRNAs of genes like BCL2 and CDK6, involved in cell cycle regulation and apoptosis. Reduced miR-34a expression has been observed in cancers like colorectal, breast, and pancreatic cancer, contributing to increased cell growth and survival.

Oncogenic miRNAs (OncomiRs)

OncomiRs promote cancer development by targeting tumor suppressor genes. A notable example is miR-21, which is overexpressed in many cancers including glioblastoma, breast cancer, and lung cancer. miR-21 targets the PTEN tumor suppressor gene, which regulates cell growth and apoptosis. Overexpression of miR-21 results in decreased PTEN levels, promoting cell survival and proliferation.

OncomiRs and their related signalling pathways in BC. As breast cancer progresses, the oncomiRs exert their regulatory effects more on the four vital signalling pathways, including Wnt/b-catenin, PI3K/Akt/mTOR/VEGF, TGF-b/Smad, and ER-a (oestrogen receptoralpha). Dysregulation and changes due to the targeting of downstream molecules in these signalling pathways can eventually lead to tumour progression and metastasis.

miRNAs in Cancer Diagnosis and Prognosis

miRNA expression profiles can be valuable tools for cancer diagnosis and prognosis. For instance, elevated miR-155 levels are associated with poor prognosis in breast cancer, while reduced levels of let-7 family miRNAs are linked to poor outcomes in lung cancer.

Therapeutic Potential of miRNAs

miRNAs have significant therapeutic potential due to their ability to regulate critical pathways involved in cancer. Therapeutic strategies include:

miRNA Mimics

Synthetic miRNAs can restore the function of downregulated tumor suppressor miRNAs. For example, miR-34 mimics are being investigated for their potential to induce apoptosis and inhibit tumor growth.

miRNA Inhibitors

Antagomirs or anti-miRNAs are synthetic molecules that inhibit oncogenic miRNAs. Inhibitors of miR-21 are being studied to restore tumor suppressor gene expression and reduce cancer cell proliferation.

Illustration of the miRNA-based drug discovery and development process beginning from target identification and miRNA discovery to FDA-approved miRNA therapeutics on the market. In the traditional drug development process, the timeline from target identification and drug discovery to phase 1–3 human clinical trials and, ultimately, FDA approval, followed by phase 4 studies, can go on for several years. Conversely, RNA-based and, more specifically, miRNA-based drug discovery and development can potentially mitigate attrition rates, time constraints, and costs. The initial phase in developing miRNA therapeutics involves systematically selecting potential miRNA candidates by analyzing patient samples and validating their relevance to a particular disease of interest through tissue culture and in vivo models. Various publicly available genomic and proteomic databases from diverse healthy and diseased tissues can aid in identifying promising miRNA candidates when combined with biological validation. The next step often involves modifying miRNA therapeutics and optimizing delivery systems suitable for in vivo applications. A major concern with miRNA therapeutics is their susceptibility to degradation by nucleases and endosomal escape. To improve the stability of miRNA therapeutics, chemical modifications such as adding a 2′-O-methyl group, 2-F group, locked nucleic acids (LNAs), or peptide nucleic acids (PNAs) as well as a phosphorothioate group considerably enhance stability. Various encapsulation methods such as lipid nanoparticles, neutral lipid emulsions, or dendrimer complexes equipped with a targeting moiety have been employed for improved delivery to target tissue and disease sites. Yet, challenges remain in transitioning these delivery systems into clinical applications due to potential immune activation effects and the lack of precise targeting for disease sites. Successful translation of lead miRNAs into clinical studies requires rigorous disease-specific in vivo testing using rodent and non-human primate models. Rigorous evaluation of toxicity data and target engagement is crucial to avert early setbacks in clinical trials.

Challenges and Future Directions

Despite the promise of miRNA-based therapies, there are challenges. Specific delivery of miRNA mimics or inhibitors to cancer cells without affecting normal tissues is a major hurdle. Additionally, understanding the complex regulatory networks in which miRNAs operate is essential for effective therapeutic development.

Future research aims to improve miRNA delivery methods, enhance the specificity and efficacy of miRNA-based treatments, and integrate miRNA profiling into clinical practice for better cancer management.

Conclusion

miRNAs are critical regulators in cancer biology, influencing various aspects of tumor development and progression. Their role as biomarkers and therapeutic targets offers significant potential for improving cancer diagnosis, prognosis, and treatment. Ongoing research into the functions and mechanisms of miRNAs will further our understanding and enhance our ability to treat cancer effectively.

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