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INTERNATIONAL CONGRESS OF

PharmacoGenetics

• MicroRNA Signaling in Cancer: Hidden Molecular Switches Controlling Tumor Growth

• Kiana hajavi,^1,* Negar khaki ,²
  1. Azad university
  2. Medical university and Azad university
  
  
  
• Introduction: Micro RNA molecules, though minuscule in size, wield enormous power over cancer development and progression. These tiny RNA fragments, typically only 18-25 nucleotides long, function as molecular switches that can activate or silence hundreds of genes simultaneously. Consequently, when microRNA regulation goes awry, cells can transform from normal to malignant, fueling uncontrolled growth and metastasis. Specifically, these non-coding RNAs regulate gene expression through binding to messenger RNA targets, thereby preventing protein translation or triggering mRNA degradation. Recent research has uncovered how tumors manipulate microRNA biogenesis through genetic mutations, epigenetic alterations, and disruptions to processing machinery. Furthermore, certain microRNAs act as tumor suppressors, while others function as oncogenes—highlighting their dual roles in cancer biology. This article examines the intricate mechanisms of microRNA biogenesis and how its disruption contributes to cancer development. We will explore the core components of microRNA processing, transcriptional alterations in tumors, mutations affecting biogenesis machinery, and regulatory pathways that modulate microRNA function. Additionally, we will analyze specific examples of microRNA dysregulation across various cancer types, providing insights into potential therapeutic targets for future cancer treatments. MicroRNA Biogenesis Pathway and Its Core Components The biogenesis of microRNAs follows a precisely orchestrated multi-step process involving specialized enzymes and protein complexes across cellular compartments. This remarkable biological assembly line transforms primary transcripts into mature microRNAs capable of regulating gene expression. Pol II-mediated pri-miRNA transcription MicroRNA biogenesis begins primarily with RNA polymerase II (Pol II) transcription, generating long primary transcripts called pri-miRNAs. These transcripts range from hundreds to thousands of nucleotides in length and contain characteristic hairpin structures [1]. The genomic origins of miRNAs vary considerably—approximately half are intragenic (located within protein- coding genes, mostly in introns), while the remainder are intergenic with independent promoters [2]. Notably, some miRNAs are transcribed as clusters from a single polycistronic transcript, often forming miRNA families with related functions [2]. Although most miRNAs are transcribed by Pol II, certain miRNAs can be transcribed by RNA polymerase III, particularly those associated with repetitive elements [3]. DROSHA–DGCR8 Microprocessor complex Once transcribed, pri-miRNAs undergo initial processing by the Microprocessor complex, composed of the RNase III enzyme DROSHA and its essential RNA-binding partner D
• Methods: Transcriptional and Epigenetic Disruption of miRNA Expression in Tumors Beyond the complex biogenesis machinery, micro RNA expression in cancer is profoundly influenced by genomic alterations and epigenetic mechanisms. These disruptions can silence tumor- suppressive miRNAs or activate oncogenic ones, creating an imbalanced microRNA landscape that promotes malignancy. Genomic deletions of miRNA loci (e.g., miR-15/16) The first connection between miRNAs and cancer emerged with the discovery of chromosome 13q14 deletions in chronic lymphocytic leukemia (CLL). This region harbors the miR-15a and miR- 16-1 cluster, which shows deleted or downregulated expression in approximately 70% of CLL cases [9]. These miRNAs regulate numerous targets involved in cell growth, apoptosis, and cell cycle control, including the anti-apoptotic protein BCL2 [9]. Indeed, the loss of miR-15/16 promotes B-cell expansion by disrupting cell cycle regulation [10]. Moreover, a germline mutation in the primary miR-15a/miR-16-1 sequence was identified in CLL patients, resulting in reduced expression levels [9]. Similarly, the miR-15b/16-2 cluster located at chromosome 3q25 exhibits tumor suppressor properties, as knockout mice develop B-cell lymphoproliferative disorders resembling human CLL [10]. Hence, chromosomal deletions represent
• Results: The intricate landscape of microRNA biogenesis and regulation represents a critical frontier in cancer biology. Throughout this article, we have examined how these tiny RNA molecules function as molecular switches with profound influence over cellular transformation. Undoubtedly, the dysregulation of microRNAs emerges through multiple mechanisms—from genomic deletions and promoter hypermethylation to specific mutations affecting processing machinery like DROSHA, DICER1, and Exportin-5. Cancer cells exploit these disruptions to silence tumor-suppressive miRNAs while amplifying oncogenic ones. For instance, the frequent deletion of miR-15/16 in chronic lymphocytic leukemia contrasts sharply with miR-17~92 amplification in B-cell lymphomas, demonstrating the dual nature of miRNA function in malignancy. Additionally, regulatory networks involving DDX proteins, SMADs, and the LIN28/let-7 axis create sophisticated control systems that tumors manipulate to sustain growth advantage.
• Conclusion: Most compelling evidence points toward miRNA signatures as potential biomarkers for cancer diagnosis and prognosis. The global downregulation of miRNAs in neuroblastoma correlates significantly with poor patient outcomes, while specific miRNA patterns distinguish high-risk from low-risk disease with remarkable accuracy. This suggests promising avenues for clinical applications. The field has progressed significantly since the first connections between miRNAs and cancer emerged. However, substantial questions remain regarding context-specific functions and therapeutic targeting strategies. As research continues, these molecular switches may become essential targets for interventions that restore normal miRNA processing or block oncogenic miRNA activity. Above all, understanding the fundamental mechanisms governing miRNA biogenesis disruption provides critical insights that will likely guide future cancer treatment paradigms.
• Keywords: Molecular cancer pharmacy micro rna genomic