miR-205 regulates basement membrane deposition in human prostate: implications for cancer development

The basement membrane (BM) is a layer of specialized extracellular matrix that surrounds normal prostate glands and preserves tissue integrity. Lack or discontinuity of the BM is a prerequisite for tumor cell invasion into interstitial spaces, thus favoring metastasis. Therefore, BM maintenance represents a barrier against cancer development and progression. In the study, we show that miR-205 participates in a network involving Delta Np63 alpha, which is essential for maintenance of the BM in prostate epithelium. At the molecular level, Delta Np63 alpha is able to enhance miR-205 transcription by binding to its promoter, whereas the microRNA can post-transcriptionally limit the amount of Delta Np63a protein, mostly by affecting Delta Np63 alpha proteasomal degradation rather than through a canonical miRNA/target interaction. Functionally, miR-205 is able to control the deposition of laminin-332 and its receptor integrin-beta 4. Hence, pathological loss of miR-205, as widely observed in prostate cancer, may favor tumorigenesis by creating discontinuities in the BM. Here we demonstrate that therapeutic replacement of miR-205 in prostate cancer (PCa) cells can restore BM deposition and 3D organization into normal-like acinar structures, thus hampering cancer progression. Cell Death and Differentiation (2012) 19, 1750-1760; doi:10.1038/cdd.2012.56; published online 4 May 2012