Abstract
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 ΔNp63α, which is essential for maintenance of the BM in prostate epithelium. At the molecular level, ΔNp63α is able to enhance miR-205 transcription by binding to its promoter, whereas the microRNA can post-transcriptionally limit the amount of ΔNp63α protein, mostly by affecting ΔNp63α 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-β4. 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.
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Abbreviations
- BM:
-
basement membrane
- ChIP:
-
chromatin immunoprecipitation
- ChIP-Seq:
-
chromatin immunoprecipitation-sequencing
- ECM:
-
extracellular matrix
- EMT:
-
epithelial-to-mesenchymal transition
- H3K27ac:
-
H3K27 histone acetylation
- H3K4me1:
-
H3K4 histone monomethylation
- H3K4me3:
-
H3K4 histone trimethylation
- ITGB4:
-
integrin-β4
- LAMA3:
-
laminin-α3
- LAMB3:
-
laminin-β3
- LAMC2:
-
laminin-γ2
- LNA:
-
locked nucleic acid
- miRNA:
-
microRNA
- NQO1:
-
NAD(P)H:quinone oxidoreductase 1
- PCa:
-
prostate cancer
- PIN:
-
prostatic intraepithelial neoplasia
- qRT-PCR:
-
quantitative reverse transcriptase PCR
- TSS:
-
transcriptional start site
- UTR:
-
untranslated region
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Acknowledgements
We thank E Campi, Dr M Pennati, and Dr M Dugo for their skilled technical assistance, and Dr L Mariani for statistical counseling. We are grateful to the Institutional Tissue Bank and to Dr S Veneroni for sample retrieval. The study was supported by AIRC (MFAG 11542), CARIPLO Foundation, I Monzino Foundation, and an ASTIL-Proche (Regione Lombardia) grant.
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Gandellini, P., Profumo, V., Casamichele, A. et al. miR-205 regulates basement membrane deposition in human prostate: implications for cancer development. Cell Death Differ 19, 1750–1760 (2012). https://doi.org/10.1038/cdd.2012.56
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DOI: https://doi.org/10.1038/cdd.2012.56
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