The other face of miR-17-92a cluster, exhibiting tumor suppressor effects in prostate cancer

Abstract

miR-17-92a cluster miRNAs are transcribed from a polycistronic transcription unit C13orf25 that generates six mature miRNAs, miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a that are overexpressed in lung and colon cancers. Here we show that the expression of miR-17-92a miRNAs are reduced in cancerous prostate tissues compared to uninvolved areas and also in aggressive prostate cancer cells. Restoration of expression of all members of miR-17-92a cluster showed, decreased expression of cell cycle regulatory proteins cyclin D1 and SSH1; and LIMK1 and FGD4 of RhoGTPase signaling pathway. Expression of miR-17-92a miRNAs caused decreased cell proliferation, reduced activation of AKT and MAP kinases, delayed tumorigenicity and reduced tumor growth in animals. Expression of miR-17-92a miRNAs inhibited EMT via reduced cell migration and expression of mesenchymal markers while elevating expression and surface localization of the epithelial marker E-Cadherin. Expression of miR-17-92a miRNAs improved sensitivity of androgen dependent LNCaP 104-S prostate cancer cells to anti-androgen drug Casodex, AKT inhibitor MK-2206 2HCl, and docetaxel. The androgen refractory PC-3 cells also showed increased sensitivity to docetaxel, MK-2206 2HCl and Aurora kinase inhibitor VX680 upon ectopic expression of miR-17-92a cluster miRNAs. Our data demonstrate a tumor suppressor effect of miR-17-92a cluster miRNAs in prostate cancer cells and restoration of expression of these miRNAs has a therapeutic benefit for both androgen-dependent and -independent prostate cancer cells.

MiR-19b non-canonical binding is directed by HuR and confers chemosensitivity through regulation of P-glycoprotein in breast cancer

“…MiR-19b has been implicated as a potential oncomiR in many cancers (Olive et al, 2009, Jin et al, 2013, and it has been assigned potential cancer-promoting functions in breast cancer via negative regulation of tumour suppressor genes such as PTEN (Li et al, 2014), PTPRG (Liu et al, 2016) and BRCA2 (Mogilyansky et al, 2016). In contrast, our data support a tumour suppressor role for miR-19b in breast epithelial cells, in accordance with some data in prostate cancer (Ottman et al, 2016) and hepatocellular carcinoma (Hung et al, 2015). HuR has also been defined as an oncogene, with higher expression associated with poor survival in breast and other cancers (Zhu et al, 2013, Denkert et al, 2004, and it is the focus of ongoing work to develop novel targeted therapeutics (Huang et al, 2016, Muralidharan et al, 2017, Wu et al, 2015.…”

MicroRNA-20a-3p and microRNA-20a-5p exhibit anti-proliferative activities in a melanoma in vitro model

“…Our findings are very similar to a study of Ottman et al, in which they showed downregulation and anti-proliferative properties of miR-20a in prostate cancer cells [25] . On the other hand, several studies demonstrated an upregulated expression of oncogenic miR-20a in other malignancies, highlighting miR-20a's heterogeneity in expression and functionality in a tissue and cell type-specific manner [26] .…”

miR‑19 in blood plasma reflects lung cancer occurrence but is not specifically associated with radon exposure

“…In the present study, changes in the level of miR-19b-3p expression were analyzed, which serve a significant role in the development of a number of cancer types (39,40), as well as in metastasis (41) and tumor response to drug therapy (42). A miRNA panel including miR-19b-3p in peripheral plasma was identified and proposed as a biomarker in diagnosis of adenocarcinoma lung cancer as reported by Zhou et al (43).…”