MiRNAs Regulating Other MiRNAs in Cancer Metastasis

Perturbation of micro RNA (miRNA) expression has been described in numerous conditions and diseases. Specifically, several reports have implicated the deregulation of certain miRNAs in cancer metastasis. Metastasis is the movement of cancerous cells away from the primary tumor to other sites of the body. This highly complicated process is thought to regulate cancer aggressiveness, and thus morbidity and mortality; making the role of miRNAs in cancer metastasis highly important, as their regulation may be a point of potential therapeutic intervention. A new study published in the journal Cell assessed the role of two specific miRNAs in regulating both global miRNA production and cancer cell metastasis.

The authors studied two miRNAs, miR-103 and miR-107, implicated in cancer. These two miRNAs were found by the authors to bind to the 3' untranslated region (UTR) of Dicer mRNA. Interestingly, Dicer is an enzyme involved in the processing of miRNA. When miR-103/107 were exogenously expressed in cells, the level of Dicer protein was concomitantly reduced as expected. The investigators suggested this may explain why miRNAs are often globally down-regulated in cancer, with a few exceptions being over-expressed.

The authors then assessed whether clinical relevance was associated with the expression profiles of these miRNAs. Interestingly, breast cancer patient samples could be divided according to low or high miR-103/107 expression. High expression was associated with a lower rate of metastasis free survival, while the opposite was true for low expression of the miRNAs. That is, expression of these miRNAs correlates with an increased chance of metastasis in breast cancer. This makes these two miRNAs potential therapeutic targets.

Using in vitro migration assays, expression of these two miRNAs could increase breast cancer cell movement in a manner that was dependent on Dicer reduction. Likewise, the injection of breast cancer cells into mice with miR-107 increased metastasis in a Dicer dependent fashion. That is, co-expression of miR-107 with exogenous Dicer prevented metastasis.

The authors found that miR-103/107 expression enhances the production of genes associated with cancer cell metastasis and promotes structural changes on the cellular level that are associated with migration. Interestingly, the miR-200 family which require Dicer for proper function, were found by the authors to be inhibited by miR-103/107. The miR-200 family, when over-expressed, could inhibit the cellular effects of miR-103/107.

This study describes two miRNAs that are deregulated in cancer to produce a metastatic phenotype. Interestingly, miR-103/107 block the processing of other miRNAs by inhibiting Dicer. From the study a potential therapeutic strategy for targeting metastatic cancer has emerged.

References:

Martello, G; et, al. A MicroRNA Targeting Dicer for Metastasis Control. Cell 141, 1195-1207, June 25, 2010.