MicroRNA Gets a Mighty Award

Abstract

Recent advancements in microRNAs (miRNAs) research have revealed their key roles in both normal physiological processes and pathological conditions, leading to potential applications in diagnostics and therapeutics. However, the path forward is fraught with several scientific and technical challenges. This review article briefly explores the milestones of the discovery, biogenesis, functions, and application for clinical diagnostic and therapeutic strategies of miRNAs. The potential challenges and future directions are also discussed to fully harness their capabilities.

Keywords: RNA biology; biomarker; cancer; miRNA; therapeutic approach.

Figure 1

Milestone discoveries in the history of miRNA research. A). The timeline of miRNA research from 1993 until 2018. It includes major events such as: 1993: Discovery of the first miRNA (lin‐4) in C. elegans.^{[ 6} , ^{7 ]} 2000: Discovery of let‐7, the second miRNA, highly conserved across animals.^{[ 2 ]} 2001: 1) miRNA officially named.^{[ 5} , ^{8 ]} 2) Discovery of Dicer, an enzyme that processes pre‐miRNA into mature miRNA.^{[ 9 ]} 2002: 1) Link between miRNA and disease is established.^{[ 3b ]} 2) First report of miRBase, providing a comprehensive miRNA database for research.^{[ 10 ]} 3) miRNA base‐pairing with the 3′ UTR of mRNA.^{[ 1a ]} 2003: 1) Discovery of Drosha, an enzyme for the nuclear processing of primary miRNA (pri‐miRNA).^{[ 3c ]} 2) The discovery of Exportin‐5 is specifically responsible for transporting pre‐miRNA from the nucleus to the cytoplasm.^{[ 12a ]} 3) It was first reported that miRNA plays an important role in embryonic morphogenesis and differentiation.^{[ 12e ]} 2004: 1) Identification of Argonaute (AGO), a key component of the RNA‐induced silencing complex (RISC).^{[ 11 ]} 2) First report of miRNAs playing an important role in the regulation of metabolism in mammals.^{[ 12b ]} 2005: First oncogenic miRNAs are reported.^{[ 12c,d ]} 2007: 1) Drosha‐independent pathway of miRNA biogenesis‐ mirtron pathway.^{[ 12f,h ]} 2) The first time that miRNA can be used as a medium of intercellular communication.^{[ 12g ]} 2008: 1) Drosha‐independent pathway of snoRNA/shRNA‐derived miRNAs.^{[ 3} , ^{26 ]} 2) Victor Ambros, Gary Ruvkun, and David Baulcombe were awarded the Lasker Foundation for their discovery of miRNAs.^{[ 13 ]} 3) miRview mets‐the earliest miRNA diagnostic kit.^{[ 12i ]} 2009: The first miRNA inhibitor miravirsen entered human clinical trials.^{[ 12j ]} 2010: 1) Drosha‐independent pathway of tRNA‐derived miRNAs.^{[ 28 ]} 2) Ago2‐mediated cleavage of miRNA biogenesis that is independent of Dicer.^{[ 29 ]} 2013: miRview mets received FDA approval. 2017: 1) 180 RNA‐binding proteins specifically interact with human pre‐miRNAs.^{[ 14 ]} 2) miRNA promotes gene expression by acting on enhances as NamiRNA.^{[ 15 ]} 2018: 1) Ago2‐mediated cleavage of miRNA biogenesis that also requires Dicer.^{[ 16 ]} 2) The first to use CRISPR‐Cas9 in miRNA detection.^{[ 17 ]} B). Recent advancements in miRNA research over the past five years. 2020: DIANA‐miRGen v4 uniquely integrates cell‐specific miRNA promoters with experimentally derived TFBSs.^{[ 18a ]} 2021: 1) A molecular model explaining how polypeptides collaborate to accurately recognize and process pri‐miRNAs.^{[ 23a ]} 2) A quantitative map of human primary microRNA processing sites.^{[ 23b ]} 2022: 1) The plasma miRNA profile at COVID‐19 and identify miRNAs as early prognostic biomarkers of severity and survival.^{[ 21 ]} 2) Reveal miRNAs encoded by herpesviruses selectively inhibit the miRNA processing of host cells.^{[ 20 ]} 2023: 1) Cryo‐electron microscopy structure of hDICER bound to pre‐miRNA in a dicing state.^{[ 19 ]} 2) The developed Exo‐PROS biosensor achieves simultaneous detection of proteins and miRNAs in exosomes originating from tumors.^{[ 22a ]} 2024: 1) Victor Ambros and Gary Ruvkun were awarded the 2024 Nobel Prize in Physiology or Medicine for their discovery of miRNA.^{[ 4 ]} 2) A computational method based on multiple hypergraph contrastive learning (MHCLMDA) to predict miRNA–disease associations.^{[ 3a ]} 3) The first comprehensive reference list of cancer‐related miRNA genes.^{[ 23c ]} 4) A novel therapeutic approach merging miRNA regulation with PROTACs' protein degradation.^{[ 18b ]} 5) Hypoxic glioma cells promote the M2 polarization of tumor‐associated macrophages by secreting exosomes rich in miR‐25‐3p.^{[ 22b ]} C). Trends of global publications on the topic of miRNA. The data are obtained from the PubMed database using the search query “(miRNA) AND (microRNA)”.

Figure 1

Milestone discoveries in the history of miRNA research. A). The timeline of miRNA research from 1993 until 2018. It includes major events such as: 1993: Discovery of the first miRNA (lin‐4) in C. elegans.^{[ 6} , ^{7 ]} 2000: Discovery of let‐7, the second miRNA, highly conserved across animals.^{[ 2 ]} 2001: 1) miRNA officially named.^{[ 5} , ^{8 ]} 2) Discovery of Dicer, an enzyme that processes pre‐miRNA into mature miRNA.^{[ 9 ]} 2002: 1) Link between miRNA and disease is established.^{[ 3b ]} 2) First report of miRBase, providing a comprehensive miRNA database for research.^{[ 10 ]} 3) miRNA base‐pairing with the 3′ UTR of mRNA.^{[ 1a ]} 2003: 1) Discovery of Drosha, an enzyme for the nuclear processing of primary miRNA (pri‐miRNA).^{[ 3c ]} 2) The discovery of Exportin‐5 is specifically responsible for transporting pre‐miRNA from the nucleus to the cytoplasm.^{[ 12a ]} 3) It was first reported that miRNA plays an important role in embryonic morphogenesis and differentiation.^{[ 12e ]} 2004: 1) Identification of Argonaute (AGO), a key component of the RNA‐induced silencing complex (RISC).^{[ 11 ]} 2) First report of miRNAs playing an important role in the regulation of metabolism in mammals.^{[ 12b ]} 2005: First oncogenic miRNAs are reported.^{[ 12c,d ]} 2007: 1) Drosha‐independent pathway of miRNA biogenesis‐ mirtron pathway.^{[ 12f,h ]} 2) The first time that miRNA can be used as a medium of intercellular communication.^{[ 12g ]} 2008: 1) Drosha‐independent pathway of snoRNA/shRNA‐derived miRNAs.^{[ 3} , ^{26 ]} 2) Victor Ambros, Gary Ruvkun, and David Baulcombe were awarded the Lasker Foundation for their discovery of miRNAs.^{[ 13 ]} 3) miRview mets‐the earliest miRNA diagnostic kit.^{[ 12i ]} 2009: The first miRNA inhibitor miravirsen entered human clinical trials.^{[ 12j ]} 2010: 1) Drosha‐independent pathway of tRNA‐derived miRNAs.^{[ 28 ]} 2) Ago2‐mediated cleavage of miRNA biogenesis that is independent of Dicer.^{[ 29 ]} 2013: miRview mets received FDA approval. 2017: 1) 180 RNA‐binding proteins specifically interact with human pre‐miRNAs.^{[ 14 ]} 2) miRNA promotes gene expression by acting on enhances as NamiRNA.^{[ 15 ]} 2018: 1) Ago2‐mediated cleavage of miRNA biogenesis that also requires Dicer.^{[ 16 ]} 2) The first to use CRISPR‐Cas9 in miRNA detection.^{[ 17 ]} B). Recent advancements in miRNA research over the past five years. 2020: DIANA‐miRGen v4 uniquely integrates cell‐specific miRNA promoters with experimentally derived TFBSs.^{[ 18a ]} 2021: 1) A molecular model explaining how polypeptides collaborate to accurately recognize and process pri‐miRNAs.^{[ 23a ]} 2) A quantitative map of human primary microRNA processing sites.^{[ 23b ]} 2022: 1) The plasma miRNA profile at COVID‐19 and identify miRNAs as early prognostic biomarkers of severity and survival.^{[ 21 ]} 2) Reveal miRNAs encoded by herpesviruses selectively inhibit the miRNA processing of host cells.^{[ 20 ]} 2023: 1) Cryo‐electron microscopy structure of hDICER bound to pre‐miRNA in a dicing state.^{[ 19 ]} 2) The developed Exo‐PROS biosensor achieves simultaneous detection of proteins and miRNAs in exosomes originating from tumors.^{[ 22a ]} 2024: 1) Victor Ambros and Gary Ruvkun were awarded the 2024 Nobel Prize in Physiology or Medicine for their discovery of miRNA.^{[ 4 ]} 2) A computational method based on multiple hypergraph contrastive learning (MHCLMDA) to predict miRNA–disease associations.^{[ 3a ]} 3) The first comprehensive reference list of cancer‐related miRNA genes.^{[ 23c ]} 4) A novel therapeutic approach merging miRNA regulation with PROTACs' protein degradation.^{[ 18b ]} 5) Hypoxic glioma cells promote the M2 polarization of tumor‐associated macrophages by secreting exosomes rich in miR‐25‐3p.^{[ 22b ]} C). Trends of global publications on the topic of miRNA. The data are obtained from the PubMed database using the search query “(miRNA) AND (microRNA)”.

Figure 2

Canonical and major non‐canonical miRNA biogenesis pathways. A) MicroRNAs are produced from genes through a canonical pathway: they are transcribed into hairpin‐shaped primary miRNAs (pri‐miRNAs), cleaved by Drosha into precursor miRNAs (pre‐miRNAs), and exported to the cytoplasm by Exportin‐5. Dicer then processes them into duplex microRNA strands, one of which is incorporated into the RNA‐induced silencing complex (RISC) to interact with mRNA. B) Non‐canonical pathways (Drosha‐independent). (Top) Mirtron Pathway: Pre‐miRNAs are generated from spliced introns instead of being processed by Drosha. These intronic sequences fold into hairpin structures and are exported to the cytoplasm for Dicer processing. (Middle) tRNA‐Derived miRNAs: Transfer RNAs (tRNAs) can also be processed into small RNA molecules, bypassing Drosha in a similar fashion. (bottom) snoRNA‐Derived miRNAs: Small nucleolar RNAs (snoRNAs) can serve as precursors for miRNAs, bypassing Drosha cleavage but still requiring Dicer for maturation. C) Non‐canonical pathways (Ago2‐cleavage dependent). (Left) Pri‐miRNA‐451 is processed by Drosha into pre‐miRNA‐451, which is directly loaded onto Ago2. Ago2's slicer activity cleaves the 3′ arm, producing ac‐pre‐miRNA‐451, which then forms mature miR‐451. (Right) MiR‐486 has perfect base‐pairing in its pre‐miRNA stem and needs Drosha, Dicer, and Ago2 to cleave the passenger strand, forming the mature single‐stranded RISC. PARN: Poly(A)‐Specific Ribonuclease.

Figure 3

Regulation mechanism and function of miRNA. A) miRNAs regulate mRNA expression. (Left) The green arrow indicates that, in the absence of miRNA, mRNA can be efficiently translated into protein before undergoing degradation. (Right) The yellow arrow signifies that, in the presence of miRNA, the translation of mRNA is inhibited, or mRNA is degraded. B–I) miRNAs are involved in normal physiological processes and pathological conditions at different levels.