MicroRNAs in cancer
This KEGG map collects the small RNA molecules (microRNAs) that are switched up or down in nine common cancers and shows which oncogenes and tumour suppressors they silence. It matters because a single microRNA can dial down dozens of genes at once, so losing or gaining one reshapes whole signalling routes.
Overview
MicroRNAs (miRNAs) are non-coding RNAs of about 21 to 23 nucleotides that control gene expression after transcription, either by degrading target messenger RNAs or by blocking their translation. KEGG map hsa05206 summarises profiling studies across nine cancers and draws two kinds of event: over-expressed miRNAs that repress tumour suppressors, and under-expressed miRNAs that release oncogenes. Both directions push proliferation, block differentiation and blunt apoptosis. KEGG notes that reported miRNA signatures differ between studies because of differences in populations and methods, so the map is a summary rather than a consensus.
Calin and Croce, Nature Reviews Cancer, 2006 (doi:10.1038/nrc1997) set out the founding evidence: miRNA genes sit at fragile sites and cancer-associated regions of the genome, the miR-15a/16-1 cluster is deleted in chronic lymphocytic leukaemia and represses BCL2, the let-7 family restrains RAS, and miR-21 and the miR-17-92 cluster are over-expressed oncogenic miRNAs. The map connects these to familiar nodes: BCL2, KRAS, PTEN (a target of miR-21), MYC (which drives miR-17-92), TP53 (which induces the miR-34 family) and E2F. Epigenetic silencing of miRNA promoters by DNA methylation and by EZH2-containing polycomb complexes is one route to miRNA loss, which is why KEGG lists the demethylating agent decitabine and the EZH2 inhibitors tazemetostat and valemetostat against this map.
What can be done: there is not yet an approved drug that directly replaces or blocks a miRNA in cancer. The practical levers today are indirect. Epigenetic drugs (decitabine, azacitidine, EZH2 inhibitors) can re-express silenced miRNAs, while drugs against the protein nodes the miRNAs control (BCL2 inhibitors, KRAS inhibitors, PI3K/AKT inhibitors) act downstream of the miRNA change. Antisense oligonucleotides against oncogenic miRNAs, such as the miR-155 inhibitor cobomarsen listed by KEGG, have reached early clinical trials.
In one picture
Think of each gene as a light in a house and microRNAs as dimmer switches wired to many lights at once. Cancer either jams a dimmer to full (silencing a whole bank of safety lights) or rips one out (so oncogene lights blaze). Because each dimmer controls many lights, fixing one switch can change the whole room.
Diagram
top- Epigenetic drugs that re-express silenced microRNAs: hypomethylating agents (decitabine, azacitidine) and EZH2 inhibitors (tazemetostat, valemetostat)
- Drugs against the protein nodes microRNAs control: BCL2 inhibitors, KRAS inhibitors (sotorasib, adagrasib), PI3K/AKT inhibitors (alpelisib, capivasertib)
- Antisense oligonucleotides against oncogenic microRNAs (miR-155 inhibitor cobomarsen), early clinical trials only
- MicroRNA signatures as diagnostic and prognostic biomarkers rather than drug targets
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