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Identification of miRNA expression profiles for diagnosis and prognosis of prostate cancer
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.ORCID iD: 0000-0001-5533-7899
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer of the prostate (CaP) is the most common malignancy diagnosed in men in the Western society. During the last years, prostate specific antigen (PSA) has been used as a biomarker for CaP, although a high PSA value is not specific for CaP. Thus, there is an urgent need for new and improved diagnostic markers for CaP.

In this thesis, the aim was to find a miRNA signature for diagnosis of CaP and to elucidate if differences in behavior between transition zone and peripheral zone tumors are reflected in miRNA expression. One of the major findings is anexpression signature based on nine miRNAs that with high accuracy (85%) could classify normal and malignant tissues from the transition zone of the prostate. The results furthermore show that the major differences in miRNA expression are found between normal and malignant tissues, rather than between the different zones. In addition, tumors arising in the peripheral zone have fewer changes in miRNA expression compared to tumors in the transition zone, indicating that the peripheral zone is more prone to tumor development compared to the transition zone of the prostate.

A crucial step in pre-processing of expression data, in order to differentiate true biological changes, is the normalization step. Therefore, an additional aim of this thesis was to compare different normalization methods for qPCR array data in miRNA expression experiments. The results show that data-driven methods based on quantile normalization performs the best. The results also show that in smaller miRNA expression studies, only investigating a few miRNAs, RNU24 is the most suitable endogenous control gene for normalization.

Taken together, the results in this thesis show the importance of miRNAs and the possibility of their future use as biomarkers in the field of prostate cancer.

Place, publisher, year, edition, pages
Örebro: Örebro universitet , 2012. , 55 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 74
Keyword [en]
Prostate cancer, microRNAs, prostate zones, normalization, endogenous controls
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-25600ISBN: 978-91-7668-888-5 (print)OAI: oai:DiVA.org:oru-25600DiVA: diva2:548438
Public defence
2012-10-26, Wilandersalen, Universitetssjukuset (USÖ), Örebro, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2012-08-30 Created: 2012-08-30 Last updated: 2017-10-17Bibliographically approved
List of papers
1. Validation of suitable endogenous control genes for expression studies of miRNA in prostate cancer tissues
Open this publication in new window or tab >>Validation of suitable endogenous control genes for expression studies of miRNA in prostate cancer tissues
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2010 (English)In: Cancer Genetics and Cytogenetics, ISSN 2210-7762, E-ISSN 2210-7770, Vol. 202, no 2, 71-75 p.Article in journal (Refereed) Published
Abstract [en]

When performing quantitative polymerase chain reaction analysis, there is a need for correction of technical variation between experiments. This correction is most commonly performed by using endogenous control genes, which are stably expressed across samples, as reference genes for normal expression in a specific tissue. In microRNA (miRNA) studies, two types of control genes are commonly used: small nuclear RNAs and small nucleolar RNAs. In this study, six different endogenous control genes for miRNA studies were investigated in prostate tissue material from the Swedish Watchful Waiting cohort. The stability of the controls was investigated using two different software applications, NormFinder and BestKeeper. RNU24 was the most suitable endogenous control gene for miRNA studies in prostate tissue materials. (C) 2010 Elsevier Inc. All rights reserved.

National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-12861 (URN)10.1016/j.cancergencyto.2010.06.009 (DOI)000282862400001 ()
Available from: 2012-09-17 Created: 2011-01-03 Last updated: 2017-12-11Bibliographically approved
2. How to choose a normalization strategy for miRNA quantitative real-time (QPCR) arrays
Open this publication in new window or tab >>How to choose a normalization strategy for miRNA quantitative real-time (QPCR) arrays
2011 (English)In: Journal of Bioinformatics and Computational Biology, ISSN 0219-7200, E-ISSN 1757-6334, Vol. 9, no 6, 795-812 p.Article in journal (Refereed) Published
Abstract [en]

Low-density arrays for quantitative real-time PCR (qPCR) are increasingly being used as an experimental technique for miRNA expression profiling. As with gene expression profiling using microarrays, data from such experiments needs effective analysis methods to produce reliable and high-quality results. In the pre-processing of the data, one cruciala nalysis step is normalization, which aims to reduce measurement errors and technical variability among arrays that might have arisen during the execution of the experiments. However, there are currently a number of different approaches to choose among and an unsuitable applied method may induce misleading effects, which could affect the subsequent analysis steps and thereby any conclusions drawn from the results. The hoice of normalization method is hence an important issue to consider. In this study we present the comparison of a number of data-driven normalization methods for TaqManlow-density arrays for qPCR and different descriptive statistical techniques that can facilitate the choice of normalization method. The performance of the normalization methods was assessed and compared against each other as well as against standard normalization using endogenous controls. The results clearly show that the data-driven methods reduce variation and represent robust alternatives to using endogenous controls.

National Category
Medical and Health Sciences Natural Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-25827 (URN)10.1142/S0219720011005793 (DOI)000297096300009 ()
Available from: 2012-09-17 Created: 2012-09-13 Last updated: 2017-12-07Bibliographically approved
3. A miRNA expression signature that separates between normal and malignant prostate tissues
Open this publication in new window or tab >>A miRNA expression signature that separates between normal and malignant prostate tissues
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2011 (English)In: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, no 11, 14- p.Article in journal (Refereed) Published
Abstract [en]

Background

MicroRNAs (miRNAs) constitute a class of small non-coding RNAs that post-transcriptionally regulate genes involved in several key biological processes and thus are involved in various diseases, including cancer. In this study we aimed to identify a miRNA expression signature that could be used to separate between normal and malignant prostate tissues.

Results

Nine miRNAs were found to be differentially expressed (p <0.00001). With the exception of two samples, this expression signature could be used to separate between the normal and malignant tissues. A cross-validation procedure confirmed the generality of this expression signature. We also identified 16 miRNAs that possibly could be used as a complement to current methods for grading of prostate tumor tissues.

Conclusions

We found an expression signature based on nine differentially expressed miRNAs that with high accuracy (85%) could classify the normal and malignant prostate tissues in patients from the Swedish Watchful Waiting cohort. The results show that there are significant differences in miRNA expression between normal and malignant prostate tissue, indicating that these small RNA molecules might be important in the biogenesis of prostate cancer and potentially useful for clinical diagnosis of the disease.

Place, publisher, year, edition, pages
BioMed Central, 2011
National Category
Natural Sciences Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-25828 (URN)10.1186/1475-2867-11-14 (DOI)000292110200001 ()21619623 (PubMedID)
Available from: 2012-09-17 Created: 2012-09-13 Last updated: 2017-12-07Bibliographically approved
4. Differences in microRNA expression during tumor development in the transition and peripheral zones of the prostate
Open this publication in new window or tab >>Differences in microRNA expression during tumor development in the transition and peripheral zones of the prostate
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background:

The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ) and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation to the difference in propensity of tumors in the zones of the prostate.

Methods:

The expression of 667 unique miRNAs was investigated in normal and malignant transition zone and peripheral zone prostate tissues using TaqMan low density arrays for miRNAs. Student’s t-test was used in order to identify differentially expressed miRNAs and hierarchical clustering and principal component analyses were used to note the separation of the tissues. A cross-validation test using the ADtree algorithm was used to test the generality of the identified miRNA signatures.

Results:

The Student’s t-tests revealed that the major differences in miRNA expression are found between normal and malignant tissues. Hierarchical clustering and PCA based on differentiallyexpressed miRNAs between normal and malignant tissues showed a perfect separation between samples while analyses based on differentially expressed miRNAs between the two zones showed several misplaced samples. A classification and cross-validation procedure confirmedt hese results and several potential miRNA markers were identified.

Conclusions:

The results of this study indicate that the major differences in the transcription programme are those arising during tumor development, rather than during normal tissue development. In conclusion, tumors arising in the TZ have more unique differentially expressed miRNAs compared to the PZ, indicating that the PZ are more prone to tumor development than the TZ. The results also indicate that separate miRNA expression signatures for diagnosis might be needed for tumors arising in the transition- or peripheral zone.

National Category
Medical and Health Sciences Natural Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-25829 (URN)
Available from: 2012-09-17 Created: 2012-09-13 Last updated: 2017-10-17Bibliographically approved

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