The Significance of microRNAs in Cancer A brief overview

Decades ago, microRNAs (miRNAs) were first identified in Caenorhabditis elegans (C. elegans) by Ambros and Ruvkun’s groups in 1993 and subsequently linked to cancer by Calin et al in 2002. This discovery sparked a surge in miRNA-related research, highlighting their pivotal role in tumourigenesis and leading to diverse applications, from biomarker development to potential RNA therapeutics. Structurally, miRNAs are small noncoding RNAs (ncRNAs), composed of single-stranded RNA molecules typically 19–24 nucleotides (nt) in length. Their biogenesis initiates in the nucleus, where primary miRNAs (pri-miRNAs) are transcribed from RNA transcripts and cleaved by RNA polymerase into precursor miRNAs (pre-miRNAs), which mature into single-stranded miRNAs approximately 22 nt long. Each step of miRNA biogenesis relies on essential components such as RNA polymerase II (Pol II) for transcription, RNase III enzymes (DROSHA and DICER1), and members of the Argonaut family (AGO2).

miRNAs play crucial roles in modulating various biological processes, exhibiting distinct spatial and temporal expression patterns. In addition to their conventional function in post-transcriptional repression of specific target proteins by promoting mRNA decay or inhibiting translation, miRNAs have been observed to influence transcriptional activation, epigenetic regulation, and upregulation of translation. In this mini-review, we aim to provide a concise overview of the role of miRNAs in cancer biology.

miRNA and cancer: a glimpse behind these two pioneers

As is widely recognized, cancer constitutes a genetic ailment affecting a growing number of individuals worldwide. It is characterised by a cascade of mutations occurring in tumour suppressor genes, facilitating uncontrolled cell proliferation, and impeding cell death. Recent findings have unveiled the role of miRNA dysregulation in bolstering cancer progression. Intriguingly, a single miRNA has the capacity to bind to numerous targets, potentially exceeding several hundred , encompassing diverse functionalities such as transcription factors, receptors, and vectors. Ample evidence underscores the marked differences in miRNA expression between normal and tumour tissues, strongly implicating their involvement in tumour progression, development, invasion, and metastasis.

Do miRNAs play a dual role?

As mentioned previously, miRNAs are implicated in modulating all cancer hallmarks, functioning either as oncogenes or tumour suppressors. However, certain miRNAs exhibit context-dependent roles, acting as oncomiRs in some malignancies while serving as tumour suppressors in others. For instance, in certain cancers, members of the let-7 family function as tumour-suppressor miRNAs, impeding invasion, metastasis, epithelial-to-mesenchymal transition (EMT), and self-renewal. Conversely, when their expression profile is elevated in the tumour microenvironment, let-7 family miRNAs can adopt oncogenic roles. Another example is miR-146a-5p, which demonstrates a dual role as both an oncomiR and a tumour suppressor in several cancers. Similarly, miR-186 exhibits a dual function, serving as both a diagnostic and therapeutic target, and playing pivotal roles in oncogenesis, cell migration, invasion, cell death, metastasis, and drug resistance. In gastrointestinal cancers, miR-9 has been identified to play a dual role as well. These observations underscore the heterogeneity of cancer and the dual role of miRNAs in malignant pathophysiology. However, further studies are imperative to elucidate the specific roles of miRNAs and the underlying mechanisms governing their regulation.

microRNAs and cancer as a full-body disease

There are studies supporting the hypothesis that miRNAs can directly modulate genes encoding hormones or enzymes responsible for hormone maturation and metabolism. Furthermore, miRNAs indirectly modulate hormone-mediated cell signaling transmission by targeting hormone antagonists or receptors.

Recent evidence suggests an important network of interactions between miRNAs and ERα (estrogen receptor-α), coordinating cellular responses to estrogen. Certain miRNAs modulated by ERα, such as (pri-) miR-17-92 and miR-206a-363, have been identified as targets that downregulate ERα expression at the protein translational level. Another study highlights the significance of miR-149-5p, which inhibits the regulatory activity of the transcription factor SP1 under 17β-estradiol therapy, while its decreased profile promotes the expression of hnRNPA1, regulating the loading of let-7 miRs into EVs. Regarding androgen receptors (AR), miR-let-7c indirectly suppresses receptor activity by targeting c-Myc. Direct associations between miR-185 and miR-205 with AR expression have been described. In prostate cancer, AR regulates the transcription of miR-21, enhancing tumour cell growth, while a confirmed connection exists between miR-185-5p and AR in clear cell renal cell carcinoma. miR-21 and miR-206 show increased expression profiles in hormone-dependent cancers.

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