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A microscopic investigation of miR-34c and miR-205 in Prostate Cancer

Hagman, Zandra LU (2012) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2012:84.
Abstract (Swedish)
Popular Abstract in Swedish

Förr trodde man att de delar av genomet som inte uttrycks till proteiner är oviktiga, eftersom man trodde att det nästan uteslutande är proteinerna som utför de nödvändiga funktionerna i cellen. Man kände till att DNA och RNA innehåller information om hur proteiner ska se ut och när de ska uttryckas, men man kände bara till ett fåtal andra uppgifter som RNA har i cellen. I och med att tekniken har utvecklats har man kunnat sekvensera det mänskliga genomet. En följd av detta var att man insåg att stora delar av genomet transkriberas till RNA utan att translateras till proteiner. Man upptäckte att det finns ett flertal grupper av RNA-strukturer, som har olika uppgifter i cellen. En av dessa grupper... (More)
Popular Abstract in Swedish

Förr trodde man att de delar av genomet som inte uttrycks till proteiner är oviktiga, eftersom man trodde att det nästan uteslutande är proteinerna som utför de nödvändiga funktionerna i cellen. Man kände till att DNA och RNA innehåller information om hur proteiner ska se ut och när de ska uttryckas, men man kände bara till ett fåtal andra uppgifter som RNA har i cellen. I och med att tekniken har utvecklats har man kunnat sekvensera det mänskliga genomet. En följd av detta var att man insåg att stora delar av genomet transkriberas till RNA utan att translateras till proteiner. Man upptäckte att det finns ett flertal grupper av RNA-strukturer, som har olika uppgifter i cellen. En av dessa grupper är mikro-RNA (miRNA) som kännetecknas av sin ringa längd (ca 20 nukleotider). miRNA kontrollerar genuttrycket genom att binda till budbärar-RNA (mRNA) och förhindra att dessa i sin tur uttrycks till proteiner. Man har idag upptäckt över 2000 olika miRNA i människan. Varje miRNA har ett flertal mRNA som den reglerar och ett mRNA kan vara reglerat av flera miRNA. miRNA har visat sig vara viktiga för att reglera olika processer i cellen såsom celltillväxt, celldöd och metabolism. Det har sedermera visat sig att mängden av olika sorters miRNA skiljer sig mellan frisk vävnad och vävnad med cancer. Man fann vidare att vissa miRNA kunde ha effekter på cellen som främjar eller motar canceruppkomst. I denna avhandling har vi visat att två miRNA, nämligen miR-34c och miR-205, uttrycks lägre i prostatacancer jämfört med frisk vävnad. Vi har kunnat se att dessa miRNA är associerade med kliniska parametrar såsom överlevnad och metastaser. Vidare har vi funnit att miR-34c har tumörhämmande egenskaper genom sin påverkan på celltillväxt, celldöd, migration och invasion. (Less)
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Prof. Steingrímsson, Eiríkur, Department of Biochemistry and Molecular Biology, University of Iceland
organization
publishing date
type
Thesis
publication status
published
subject
keywords
microRNA, prostate cancer, androgen receptor, MET, HGF, miR-34c, miR-205, AGO2-RIP-Chip, noncoding RNA
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2012:84
pages
150 pages
publisher
Department of Laboratory Medicine, Lund University
defense location
CRC aulan, SUS, Malmö
defense date
2012-10-31 09:00
ISSN
1652-8220
ISBN
978-91-87189-47-0
language
English
LU publication?
yes
id
28317e5b-dfed-4a31-b9b7-06e72a85f9ee (old id 3127698)
date added to LUP
2012-10-10 09:07:37
date last changed
2016-09-19 08:44:46
@phdthesis{28317e5b-dfed-4a31-b9b7-06e72a85f9ee,
  abstract     = {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. <br/><br>
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.<br/><br>
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. <br/><br>
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.},
  author       = {Hagman, Zandra},
  isbn         = {978-91-87189-47-0},
  issn         = {1652-8220},
  keyword      = {microRNA,prostate cancer,androgen receptor,MET,HGF,miR-34c,miR-205,AGO2-RIP-Chip,noncoding RNA},
  language     = {eng},
  pages        = {150},
  publisher    = {Department of Laboratory Medicine, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {A microscopic investigation of miR-34c and miR-205 in Prostate Cancer},
  volume       = {2012:84},
  year         = {2012},
}