Increases in Dicer gene expression improve some cancers and worsen others
Some of the tiniest players on the field, microRNAs (miRNAs) are short strands of RNA that work to control gene expression in several pathways. Though they don’t encode any proteins, miRNAs regulate genes involved in embryonic growth, cell differentiation, angiogenesis and other cellular processes. They have also gained steady prominence in cancer research, with several studies connecting abnormal miRNA regulation to cancer progression and metastasis in cell lines, animal models and samples from patients.
The potential diagnostic and therapeutic value of miRNAs has also turned attention to the molecules involved in making miRNAs in cells, particularly the enzyme Dicer. A recent study by Zhihai Ma and colleagues in PLoS One reports that higher Dicer expression correlates to more advanced stages of cutaneous melanoma, characterized by increased metastatic potential, tumor mitotic index, and other stages (as defined by the American Joint Committee on Cancer) .
Other studies have identified specific miRNAs linked to enhanced proliferation, metastatic potential, post-recurrence survival of patients, etc. but this is the first research examining the correlation of Dicer levels, rather than miRNA profiles, to melanoma progression.
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Comparing amounts of the Dicer protein in over 400 samples of different kinds of skin cancers, Ma et al. found that Dicer levels were significantly greater in cutaneous melanomas than in carcinomas, sarcomas or benign melanocytic nevi. Testing the location and amounts of the Dicer protein inside cancer cells, the authors discovered that normal skin keratinocytes express Dicer at consistently low levels. Different kinds of carcinomas and sarcomas also express low levels of the protein, but primary cutaneous and metastatic melanoma cells showed high levels of Dicer. Amongst melanocytic tumors, nevus cells and mucosal melanomas had lower levels of the protein than cutaneous, acrolentiginous and metastatic melanomas.
The authors support these results by mining existing research on the RNA expression profiles of genes involved in miRNA synthesis and processing in cells. Using NextBio, they pooled data from two studies on expression patterns of all the enzymes involved in miRNA synthesis and processing in cells, combining data from over 25,000 genes spanning 20 disease groups, including normal skin and several cutaneous cancers. Here, Dicer ranked among the top 20% of all significant genes, and was expressed 2.5 fold higher in cutaneous melanomas than in basal cell carcinomas.
Overall, their results show that an increase in Dicer expression strongly correlates to metastatic and more severe forms of cutaneous melanoma rather than normal skin or benign nevi. This research adds to a growing body of evidence associating Dicer to cancer in patient tumor samples.
Dicer is already considered a prominent, albeit confusing, player in prostate, lung, breast, ovarian and several other cancer types. In some cancers, like prostate adenocarcinomas, an increase in Dicer expression is linked to poor prognosis, whereas in others, such as lung and ovarian carcinomas, lower Dicer expression is linked to more severe disease. These contradictory observations are particularly important since most of these studies conclude that Dicer expression is a strong candidate biomarker or potential drug target.
Experiments in mouse models offer a potential explanation of Dicer mechanisms in cancer. Two recent studies created mouse mutants of Dicer to test the effects of the mutation on retinoblastoma, a kind of eye cancer. Both studies, one by Kumar et al. and the other by Lambertz et al., identify a dosage-dependent effect of Dicer. In their experiments, knocking out one copy of the Dicer gene enhanced tumor formation in the mice, but knocking out both copies led to suppression of tumor formation. Their results suggest that partial loss of Dicer function favors tumor formation, while completely eliminating Dicer expression suppresses tumor formation, at least in retinoblastomas. Though these studies suggest one explanation, several other possibilities exist (tissue-specific effects being the most obvious) and need to be verified experimentally.
So far, research on the role of Dicer in human cancers has largely focused on establishing correlations between Dicer levels and cancer prognosis. Studies like the cutaneous melanoma research described here add to this understanding of Dicer levels in different kinds of cancers and increase the possibility of Dicer being used as a potential drug target, biomarker or diagnostic tool. In this context, a better understanding of the mechanisms by which Dicer and its product miRNAs exert their effects in human cancers is especially critical.
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