A microscopic investigation of miR-34c and miR-205 in Prostate Cancer
Sammanfattning: The complex genetics of cancer allows tumors to grow and spread undeterred by the control mechanisms of the cell. The importance of protein-coding genes in tumorigenesis is well established. Recently, microRNAs (miRNAs) have emerge as key regulator of development and cellular processes such as differentiation, cell growth and cell death; processes closely linked to cancer. The aim of this thesis was to study the impact of miRNAs in prostate cancer. We show that the expression of miR-34c is downregulated in prostate cancer and inversely associated to shortened overall survival, aggressiveness of the tumor, WHO grade, and occurrence of metastases. The potential of miR-34c being a tumor suppressor in prostate cancer was investigated in vitro. Ectopic expression of miR-34c decreased cell growth, due to an effect on proliferation and apoptosis. Further, ectopic expression of miR-34c suppressed migration and invasion. In a screen of miRNAs regulating the androgen receptor, miR-34c was identified, and shown to inversely correlate to androgen receptor immunostaining in prostate cancer patients. Identification of additional miR-34c targets was performed and one of the identified targets was MET, a receptor tyrosine kinase that is crucial for metastasis. These results suggest that miR-34c has potential as a therapeutic tool in prostate cancer, since it has tumor suppressive functions and target important oncogenes. The prognostic properties of miR-205 were investigated and it was shown that the expression of miR-205 was inversely associated to shortened overall survival and occurrence of metastasis. In situ hybridization was performed, demonstrating high miR-205 expression in the basal cells of benign prostate tissue glands. Ectopic expression of miR-205 decreased the level of androgen receptor in prostate cancer cells. By a luciferase reporter assay we show that miR-205 directly targets the androgen receptor. This is corroborated in a prostate cancer cohort were miR-205 is found to be significantly lower in castration resistant prostate cancer patients than in hormone naïve patients. Furthermore, miR-205 expression levels are inversely correlated to androgen receptor immunostaining, suggesting that endogenous miR-205 affect the androgen receptor in vivo. Our findings suggest that miR-34c and miR-205 have potential as diagnostic markers, since their expression is associated with important clinical parameters such as the aggressiveness of the disease and metastasis.
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