miRNA-708 Control of CD44(+) Prostate Cancer-Initiating Cells
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.
Article: MicroRNAs and cancer[Show abstract] [Hide abstract]
ABSTRACT: The review is devoted to analyzing the data on the role of microRNAs in human tumor progression. The following topics are thoroughly discussed in the review: (1) general characteristics of microRNAs; (2) their expression pattern in human tumors and specificity of this expression; (3) the possible role of microRNAs as oncogenes and tumor growth suppressors; and (4) their participation in the processes responsible for the transformed phenotype of tumor cells; and (5) the role of microRNAs in early diagnostics of the disease and its prognosis.Molecular Biology 03/2014; 48(2):197-206. DOI:10.1134/S0026893314020083 · 0.74 Impact Factor
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ABSTRACT: There remains a great need for effective therapies for lung cancer, the majority of which are non-small-cell lung cancers (NSCLC). Here we report the identification of a novel candidate therapeutic target, LunX, as a molecule overexpressed in primary NSCLC and lymph node metastases that is associated with reduced postoperative survival. Functional studies demonstrated that LunX overexpression promoted lung cancer cell migration and proliferation by interactions with the chaperone protein 14-3-3. Conversely, LunX silencing disrupted primary tumor growth, local invasion and metastatic colonization. The finding that LunX was expressed on cell membranes prompted us to generate and characterize LunX antibodies as a candidate therapeutic. Anti-LunX could downregulate LunX and reduce lung cancer cell proliferation and migration in vitro. Administered in vivo to mice bearing lung cancer xenografts, anti-LunX could slow tumor growth and metastasis and improve mouse survival. Together, our work provides a preclinical proof of concept for LunX as a novel candidate target for immunotherapy in lung cancer. Copyright © 2015, American Association for Cancer Research.Cancer Research 01/2015; 75(6). DOI:10.1158/0008-5472.CAN-14-1831 · 9.28 Impact Factor
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ABSTRACT: Glucocorticoids are widely used in conjunction with chemotherapy for ovarian cancer to prevent hypersensitivity reactions. Here we reveal a novel role for glucocorticoids in the inhibition of ovarian cancer metastasis. Glucocorticoid treatments induce the expression of miR-708, leading to the suppression of Rap1B, which result in the reduction of integrin-mediated focal adhesion formation, inhibition of ovarian cancer cell migration/invasion and impaired abdominal metastasis in an orthotopic xenograft mouse model. Restoring Rap1B expression reverts glucocorticoid-miR-708 cascade-mediated suppression of ovarian cancer cell invasion and metastasis. Clinically, low miR-708 and high Rap1B are found in late-state ovarian tumours, as compared with normal, and patients with high miR-708 show significantly better survival. Overall, our findings reveal an opportunity for glucocorticoids and their downstream mediators, miR-708 or Rap1B, as therapeutic modalities against metastatic ovarian epithelial cancer.Nature Communications 01/2015; 6:5917. DOI:10.1038/ncomms6917 · 10.74 Impact Factor