An exciting new study shows that a microRNA called miR-21 acts as an oncogene to promote squamous cell carcinoma of the skin, and its up-regulation is dependent on reduced expression of the transcription factor Grhl3.
MicroRNAs were previously introduced here using the Let7 family as an example. Many different microRNAs are down- or up-regulated in tumour cells and can act as tumour suppressors or oncogenes Oncogenic miRNAs (oncomirs) are attractive targets for therapeutic intervention as therapeutics can be developed to inhibit their function. A group from the University of California in Irvine CA, USA looked at the epidermis of mice which have the transcription factor Grhl3 genetically deleted. They observed a significant change in a number of microRNAs (Table 1), interestingly three of these were up-regulated 2 fold or more. miR-21, up-regulated to the greatest extent (2.5 +/- 0.6 fold increase), was one of the first oncomirs to be discovered and many of the proteins that it targets for degradation are tumour suppressors. Enforced loss of Grhl3 clearly led to a significant increase in miR-21 expression in the mouse model and importantly in isolated normal human epidermal keratinocytes, the main cell types in the human epidermis.
The group then showed that Grhl3 directly binds to the region of DNA that precedes miR-21, this region normally acts to promote the expression of for miR-21, however Grhl3 binding prevents the function of the miR-21 promoter. Therefore, loss of Grhl3 would remove this promoter repression and allow for the increased miR-21 expression as observed in Grhl3 deficient mice.
Short RNA sequences called antagomirs can be used to inhibit miRNAs including miR-21. When mice were treated with an miR-21 antagomir, reduced miR-21 expression was observed. The group next investigated which genes are targeted by miR-21 a cell line representative of human keratinocytes and karatinocyte tumour cells. These included tumour-suppressor genes involved in the cell cycle such as Cdk6 and Cdc25, and a protein responsible for repairing damaged DNA called Msh2 that is frequently mutated in cancer.
The effect of miR-21 on these genes was more significant when kerantinocytes were transformed into tumourous cells. The group observed that transformation of kerantinocytes also caused down-regulation of a protein called DND1, DND1 it turns out is a negative regulator of the function of miR-21. Artificial over-expression of DND1 in transformed keratinocytes prevents miR-21 induced down-regulation of Msh2. Conversely, an artificial decrease in DND1 expression caused an enhancement of miR-21 induced Msh2 down-regulation.
The importance of Grhl3 and Msh2 in the progression of skin cancer was highlighted when the group investigated the ability of keratinocytes lacking Grhl3 to form tumours in mice. Loss of Grhl3 caused an increase in tumour volume an importantly was associated with loss of Msh2, showing the importance of this new epidermal regulatory pathway in skin cancer.
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