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

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 DNp63a, which is essential for maintenance of the BM in prostate epithelium. At the molecular level, DNp63a is able to enhance miR-205 transcription by binding to its promoter, whereas the microRNA can post-transcriptionally limit the amount of DNp63a protein, mostly by affecting DNp63a 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-b4. 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. MicroRNAs (miRNAs) are short, non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. 1 By hybridizing to at least partially complementary regions on target mRNAs, miRNAs can induce mRNA degradation or translation inhibition, thus finely tuning protein expression in a variety of biological processes. 1 Consequently, aberrant miRNA expression and function have been linked to the pathogenesis of human diseases, including cancer, where specific miRNAs have been proven to act as oncogenes or tumor suppressors. 2 We previously showed that miR-205 is downregulated in prostate cancer (PCa) compared with adjacent non-neoplastic tissue. 3 This finding was then confirmed by several independent studies (reviewed in Gandellini et al. 4 ; Schaefer et al. 5 ), and miR-205 recognized as the best single miRNA able to correctly distinguish prostate tumor from normal tissue. 6 We also reported that miR-205 acts as a tumor suppressor in human prostate, as its reintroduction in PCa cells reverts epithelial-to-mesenchymal transition (EMT), 3 thus suggesting that miR-205 reduction may drive the progression toward a cell phenotype with enhanced invasive properties and favor metastasis. Accordingly, tumors from patients with lymph node dissemination show lower miR-205 expression than those from node-negative patients. 3 However, evidence of a downregulation of the miRNA in clinically localized carcinomas 4 suggests that loss of miR-205 in PCa may anticipate disease progression. To gain insight into this early loss of the miRNA and into the mechanisms of PCa development, we investigated the physiological role of miR-205 in normal prostate.Prostatic epithelium is characterized by three different cell layers: (i) an outer, androgen-independent basal layer, lying on a basement m...

The p63 Protein Isoform ΔNp63α Inhibits Epithelial-Mesenchymal Transition in Human Bladder Cancer Cells

“…Furthermore, there was no correlation between the mutational status of p53 and the expression of miR-205 (or for that matter members of the miR-200 family) in our BC cell lines (46), suggesting that p53 is not centrally involved in maintaining expression of these epithelial micro RNAs in BC cells. Importantly, our conclusions regarding the importance of ⌬Np63␣ in regulating miR-205 expression are consistent with recent work in prostate cancer cells (47).…”

P63 in health and cancer

“…The miR-200 family controls the epithelial-mesenchymal transition (EMT). EMT is a typical mechanism to promote cancer invasiveness and metastasis (Gandellini et al, 2012). The miR-200 family represses transcription of ZEB1 (E-cadherin transcriptional repressor) and ZEB2.…”

Detecting cancer biomarkers in blood: challenges for new molecular diagnostic and point-of-care tests using cell-free nucleic acids

“…miRNAs also have roles in the cellular response to chemotherapy as well as cell adhesion and metastasis, which makes them a particularly promising set of biomarkers for cancer [70][71][72][73][74][75][76][77]. The discovery that altered levels of miRNAs are associated with certain cancers, including pulmonary, liver and ovarian cancer, has turned focus to the use of miRNA as a new, powerful diagnostic and prognostic tool [78][79][80][81].…”