MicroRNAs and metastasis: small RNAs play big roles

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs regulating post-transcriptional gene expression. They play important roles in many biological processes under physiological or pathological conditions, including development, metabolism, tumorigenesis, metastasis, and immune response. Over the past 15 years, significant insights have been gained into the roles of miRNAs in cancer. Depending on the cancer type, miRNAs can act as oncogenes, tumor suppressors, or metastasis regulators. In this review, we focus on the role of miRNAs as components of molecular networks regulating metastasis. These miRNAs, termed metastamiRs, promote or inhibit metastasis through various mechanisms, including regulation of migration, invasion, colonization, cancer stem cell properties, epithelial-mesenchymal transition, and microenvironment. Some of these metastamiRs represent attractive therapeutic targets for cancer treatment.

Keywords: MetastamiR; Metastasis; MicroRNA (miRNA); OncomiR.

Figure 1. Schematic representation of miRNA biogenesis

In the nucleus, the primary miRNA transcript (pri-miRNA), produced by RNA polymerase II or III, is cleaved by the microprocessor complex Drosha–DGCR8. The resulting hairpin-shaped precursor (pre-miRNA) is exported from the nucleus by Exportin-5–Ran-GTP. In the cytoplasm, the RNase Dicer, paired with the double-stranded RNA-binding protein TRBP, cleaves the pre-miRNA into the miRNA duplex of mature length. The functional strand of the duplex is loaded together with Argonaute (AGO) proteins into the RNA-induced silencing complex (RISC), where it guides RISC to silence target RNAs through RNA cleavage and/or translational inhibition.

Figure 2. Mechanisms by which miRNAs regulate metastasis

MetastamiRs can function through regulation of oncogenes, tumor suppressor genes, metastasis genes, cancer stem cell properties, epithelial-mesenchymal transition (EMT), microenvironment, and exosome secretion. Regulators of miRNA biogenesis also play functional roles in metastasis.

Figure 3. Model of miR-10b-mediated regulation of tumorigenesis and metastasis

The first metastamiR, miR-10b, downregulates multiple tumor suppressors or metastasis suppressors, ultimately contributing to malignant progression.

Figure 4. Regulation and mechanism of action of Dicer in metastasis

Dicer’s positive regulators TAp63 and KDM6A/B suppress metastasis, and its negative regulators miR-103/107 and miR-630 promote metastasis. Downregulation of Dicer attenuates the biogenesis of miRNAs including miR-200, leading to derepression of ZEB1 and induction of EMT, invasion, and metastasis.

Figure 5. miRNAs suppress bone metastasis by inhibiting osteoclastogenesis

miR-34a targets transforming growth factor-β-induced factor 2 (Tgif2), while miR-133a, miR-141, and miR-219 target Mitf in pre-osteoclasts, leading to inhibition of osteoclastogenesis and reduced osteolytic bone metastasis.

Figure 6. miRNAs regulate metastasis through exosome secretion

(A) Tumor cell-secreted exosomal miRNAs enter niche cells (e.g., endothelial cells) in the microenvironment to promote migration, invasion, and metastasis. (B) Niche cell-secreted exosomal miRNAs (e.g., astrocyte-derived exosomal miR-19a) enter metastasized tumor cells to promote metastatic outgrowth.