Section of lung isolated from mice injected with miR-10b-transduced infected cells, at week 9 after transplantation. Circles indicate clusters of metastatic cells.

From Nature 449, 682-688 (2007).

MicroRNAs (miRNAs) are small non-coding RNAs that silence gene expression by either cleaving target mRNAs or inhibiting their translation. miRNA pathways appear to be implicated in the regulation of many cellular processes, and now, in Nature, Weinberg and colleagues report that miR-10b promotes cancer metastatic spread.

From a group of miRNAs previously reported to be differentially expressed between breast carcinomas and normal tissue, Li Ma in Weinsberg's group identified miR-10b as being upregulated exclusively in metastatic cells. To test the causal role of miR-10b in breast cancer metastasis, an in vitro Matrigel invasion assay was performed. Whereas silencing of miR-10b led to a substantial reduction in the invasive properties of breast cancer cells, its ectopic expression was sufficient to increase motility and invasiveness.

Given that miR-10b is required for invasive migration in vitro, a key question was whether miR-10b could also affect the dissemination of cancer in vivo. Non-metastatic human breast cancer cell lines were manipulated to express increased levels of miR-10b and implanted into mouse mammary fat pads. The control and miR-10b-overexpressing primary tumours grew to comparable sizes, but only miR-10b-overexpressing cells metastasized, showing that miR-10b is sufficient to confer invasiveness on some cancer cells. In addition, miR-10b promoted tumour angiogenesis.

Remarkably, the authors were able to characterise the signalling pathway through which miR-10b potentially regulates metastasis by identifying both an upstream regulator of miR-10b and a downstream target.

Following the assumption that the gene encoding miR-10b is likely to be a target of transcription factors known to be specifically activated in metastatic cells, the authors found that overexpressing the pro-metastatic transcription factor Twist in mammary epithelial cells induced mir-10b. Twist interacted with the putative mir-10b promoter, strongly suggesting it directly regulates regulate miR-10b. This idea was further reinforced by the finding that miR-10b inhibition impaired the capacity of Twist to promote invasion.

Using computational methods, Weinberg and colleagues identified around 100 potential miR-10b target genes. HOXD10 was of particular interest, given its known link to cell migration and tumour progression. Li Ma showed that miR-10b inhibits HOXD10 translation by binding to the 3' untranslated region (UTR) of its mRNA. Notably, overexpression of a HOXD10-encoding mRNA able to resist the translational inhibition completely abrogated miR-10b-induced invasiveness, proving that HOXD10 is indeed a functional target of miR-10b. The authors also found that miR-10b increased RHOC expression, which is known to be repressed by HOXD10 and to stimulate cancer metastasis.

Altogether, Weinberg and colleagues identified a miRNA-mediated pathway that regulates cancer metastasis. They report that Twist-induced miR-10b inhibits the synthesis of the HOXD10 protein and that this, in turn, increases the expression of RHOC, thus favouring invasive migration. It will be important to assess the extent to which other miRNAs pathways are involved in controlling cancer spread, and if therapeutic strategies that target miRNAs may be suitable for its prevention.

Author: Kim Baumann