A microscopic investigation of miR-34c and miR-205 in Prostate Cancer
Author
Summary, in English
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.
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.
Department/s
- Clinical Chemistry, Malmö
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2012
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2012:84
Full text
- Available as DOC - 755 kB
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Document type
Dissertation
Publisher
Department of Laboratory Medicine, Lund University
Topic
- Medicinal Chemistry
Keywords
- microRNA
- prostate cancer
- androgen receptor
- MET
- HGF
- miR-34c
- miR-205
- AGO2-RIP-Chip
- noncoding RNA
Status
Published
Research group
- Clinical Chemistry, Malmö
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-87189-47-0
Defence date
31 October 2012
Defence time
09:00
Defence place
CRC aulan, SUS, Malmö
Opponent
- Eiríkur Steingrímsson (Prof.)