miRNA-708 Control of CD44(+) Prostate Cancer-Initiating Cells

ArticleinCancer Research 72(14):3618-30 · May 2012with19 Reads
DOI: 10.1158/0008-5472.CAN-12-0540 · Source: PubMed
Abstract
Tumor recurrence in prostate cancer has been attributed to the presence of CD44-expressing tumor-initiating cells. In this study, we report that miR-708 is a key negative regulator of this CD44(+) subpopulation of prostate cancer cells, with important implications for diagnosis and prognosis of this disease. miR-708 was underexpressed in CD44(+) cells from prostate cancer xenografts. Reconstitution of miR-708 in prostate cancer cell lines or CD44(+) prostate cancer cells led to decreased tumorigenicity in vitro. Intratumoral delivery of synthetic miR-708 oligonucleotides triggered regression of established tumors in a murine xenograft model of human prostate cancer. Conversely, miR-708 silencing in a purified CD44(-) population of prostate cancer cells promoted tumor growth. Functional studies validated CD44 to be a direct target of miR-708 and also identified the serine/threonine kinase AKT2 as an additional target. Clinically, low miR-708 expression was associated significantly with poor survival outcome, tumor progression, and recurrence in patients with prostate cancer. Together, our findings suggest that reduced miR-708 expression leads to prostate cancer initiation, progression, and development by regulating the expression of CD44 as well as AKT2. miR-708 therefore may represent a novel therapeutic target or diagnostic and prognostic biomarker in prostate cancer.
    • "We showed that miR-708 is a key negative regulator of the CD44(+) subpopulation of prostate cancer cells by directly regulating CD44 [129]. Also, miR-708 directly targets Akt2, a component of the PI3K/Akt pathway, with roles in tumor progression and CSCs [129]. "
    [Show abstract] [Hide abstract] ABSTRACT: Prostate cancer (PCa) is a leading cause of male cancer-related deaths. A significant fraction of prostate tumors are very aggressive, often metastasizing to bone, causing significant morbidity and mortality. Also, PCa is associated with high rates of recurrence, often attributed to the existence of cancer stem cells. Epithelial-mesenchymal transition (EMT), a process characterized by decreased expression of epithelial genes and increased expression of mesenchymal genes, plays a critical role in tumor invasion, metastasis and recurrence. In PCa, EMT has been implicated particularly in the context of metastatic disease and microRNAs have emerged as critical post-transcriptional regulators of PCa EMT. In this review, we summarize the role of miRNAs in PCa EMT that play a role in progression, metastasis and recurrence. Studies till date suggest that microRNAs mediate efficient and reversible control of PCa EMT via multiple mechanisms including either by (i) directly repressing single or multiple EMT-TFs or regulating cytoskeletal components (epithelial/mesenchymal genes) or (ii) regulating key signaling pathways involved in EMT. Oncogenic microRNAs often act as EMT promoters by repressing epithelial characteristics and tumor suppressive miRNAs act by inhibiting mesenchymal progression. Further, EMT is mechanistically linked to stem cell signatures in PCa and several miRNAs implicated in EMT have been reported to influence PCa stem cells. Loss of EMT-inhibiting miRNAs and/or gain of EMT promoting miRNAs lead to induction of PCa EMT, leading to tumor progression, metastasis and recurrence. Restoring expression of tumor suppressive miRNAs and inhibiting oncogenic miRNAs represent potential therapeutic opportunities to prevent disease metastasis and recurrence.
    Article · Aug 2016
    • "Mechanistically, we find that like miR-34a, which is also under-expressed in CD44 + PCSCs [9], miR-199a-3p directly targets CD44 in several PCa cell types. The fact that 3 tumor-suppressive miRNAs, i.e., miR-34a [9], miR-708 [28] , and miR-199a- 3p (this study), simultaneously target 5 different sites at the CD44 3'-UTR (Figure 6A), highlights the critical importance of CD44 in regulating CSC properties [6][7][8][9][10]. Notably, our present study has provided evidence that miR-199a-3p may also exert tumor-suppressive functions via modulating several novel targets, i.e., c-MYC, cyclin D1, and EGFR. "
    [Show abstract] [Hide abstract] ABSTRACT: Human cancers exhibit significant cellular heterogeneity featuring tumorigenic cancer stem cells (CSCs) in addition to more differentiated progeny with limited tumor-initiating capabilities. Recent studies suggest that microRNAs (miRNAs) regulate CSCs and tumor development. A previous library screening for differential miRNA expression in CD44 + (and other) prostate CSC vs. non-CSC populations identified miR-199a-3p to be among the most highly under-expressed miRNAs in CSCs. In this study, we characterized the biological functions of miR-199a-3p in CD44 + prostate cancer (PCa) cells and in tumor regeneration. Overexpression of miR-199a-3p in purified CD44 + or bulk PCa cells, including primary PCa, inhibited proliferation and clonal expansion without inducing apoptosis. miR-199a-3p overexpression also diminished tumor-initiating capacities of CD44 + PCa cells as well as tumor regeneration from bulk PCa cells. Importantly, inducible miR-199a-3p expression in pre-established prostate tumors in NOD/SCID mice inhibited tumor growth. Using target prediction program and luciferase assays, we show mechanistically that CD44 is a direct functional target of miR-199a-3p in PCa cells. Moreover, miR-199a-3p also directly or indirectly targeted several additional mitogenic molecules, including c-MYC, cyclin D1 (CCND1) and EGFR. Taken together, our results demonstrate how the aberrant loss of a miRNA-mediated mechanism can lead to the expansion and tumorigenic activity of prostate CSCs, further supporting the development and implementation of miRNA mimics for cancer treatment.
    Full-text · Article · Aug 2016
    • "Further investigation into the cross-talk between CD44 and inflammatory signaling in ovarian cancer will hopefully lead to a better understanding of more effective focal points for therapeutic intervention. Moreover, post-transcriptional regulation of CD44 by multiple non-coding RNAs (ncRNA) including miRNAs and lncRNAs have been described in hepatocellular carcinoma [74], osteosarcoma [75], prostate cancer [76,77], and gastric cancer [78,79]. Although miR-199a was reported to target CD44 in ovarian cancer [68], additional studies are needed to further characterize these CD44 regulatory mechanisms in epithelial ovarian cancer. "
    [Show abstract] [Hide abstract] ABSTRACT: CD44, a cell surface glycoprotein, has been increasingly implicated in the pathogenesis and progression of epithelial ovarian cancer, the deadliest gynecologic malignancy in women. Here, we review recent reports on the expression and function of CD44 in epithelial ovarian carcinoma. Further functional data for CD44 in peritoneal adhesion and metastatic progression and its association with stem cells is highlighted. Recent studies utilizing CD44 for therapeutic targeting are also discussed.
    Full-text · Article · Nov 2015
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