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.
Highlights
Despite many advances, clinical management of prostate cancer remains a major challenge and this disease continues to represent a leading cause of cancer-related morbidity and mortality [1]
CD44 is a functional target of miR-708 in prostate cancer Because CD44 is an important marker that determines tumorigenic behavior of prostate cancer cells, it is essential to elucidate regulatory mechanisms that converge on this molecule. miRNAs constrain gene expression by binding to the 30-untranslated region (UTR) of cognate mRNA targets [20]
To test the potential regulation of CD44 by miR-708, we purified CD44þ and CD44À subpopulations of prostate cancer cells from 2 prostate cancer xenograft mouse models (PC3 and LAPC9) followed by miR-708 expression profiling (Fig. 1B). miR-708 expression was significantly downregulated in CD44þ versus CD44À cells suggesting that miR-708 regulates the CD44þ subpopulation in prostate cancer
Summary
Clinical management of prostate cancer remains a major challenge and this disease continues to represent a leading cause of cancer-related morbidity and mortality [1]. A major challenge in prostate cancer diagnosis is posed by the inability of current diagnostic methods, including prostate-specific antigen (PSA) screening and histopathologic grading, to distinguish between indolent and aggressive tumors. There is an urgent need to identify alternate prostate disease biomarkers with better prognostic and diagnostic potential. Another challenging aspect of prostate cancer is the high rates of recurrence associated with the disease. About 40% of men with localized prostate cancer suffer from relapse after initial therapy [4]. In these cases, androgen ablation therapy is used to reduce tumor burden/circulating PSA to low or undetectable limits.
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