Umeå University's logo

umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
The microRNA landscape of prostate cancer bone metastases and the role of miRNA-375 in modulating phenotypic characteristics of metastatic cells
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.ORCID iD: 0009-0002-0666-8952
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.ORCID iD: 0000-0001-5394-7239
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Show others and affiliations
(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Research subject
Pathology; Pathology
Identifiers
URN: urn:nbn:se:umu:diva-215545OAI: oai:DiVA.org:umu-215545DiVA, id: diva2:1806551
Available from: 2023-10-23 Created: 2023-10-23 Last updated: 2023-10-23
In thesis
1. MicroRNA expression profiles in prostate cancer bone metastases: functional effects of microRNA-23c, -375, and -4328
Open this publication in new window or tab >>MicroRNA expression profiles in prostate cancer bone metastases: functional effects of microRNA-23c, -375, and -4328
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Non-coding microRNAs (miRNAs) function as post-transcriptional regulators of gene expression by interacting with messenger RNA. Dysregulation of miRNAs has many possible consequences, including tumor-suppressive or -promoting ones, and restoring or preventing the effects of miRNA alteration has therapeutic potential.

Metastatic prostate cancer (PC) spreads to the bone and is treated with castration therapy. Eventually, metastases relapse into castration-resistant PC (CRPC) growth. Recently, our laboratory described metastatic PC subtypes, termed MetA-C, defined based on transcriptomic differences and linked to different morphology and prognosis. Patients with MetB metastases have particularly poor prognosis.

The overall aim of the thesis was to identify novel biomarkers and therapeutic targets for metastatic PC, with a focus on miRNAs. The specific aims were to: (1) identify miRNAs associated with PC progression into bone metastasis, and their functional roles; (2) verify the MetA-C subtypes, their prognostic importance, and their relation to genetic profiles in independent validation cohorts; (3) explore miRNA expression profiles of PC bone metastases, specifically in relation to the MetA-C subtypes, and whether specific miRNAs show potential to inhibit the aggressive MetB subtype.

Study 1: Differentially expressed miRNAs (n=79) were identified by microarray analysis by comparing miRNA levels in bone metastatic (n=14) or localized PC (n=7) samples to benign samples (n=7). Downregulation of miRNA-23c and -4328 was verified by qRT-PCR analysis, including a larger cohort of bone metastases (n=67).  Overexpression of miRNA-23c or -4328 in PC cells resulted in attenuated cell growth in vitro. High levels of miRNA-23c were detected in extracellular vesicles shed from overexpressing cells. Overexpression of miRNA-23c did not obviously affect tumor growth or angiogenesis in vivo.  

Study 2: The existence and prognostic value of the MetA-C subtypes was verified by transcriptomic analysis of bone metastasis samples (n=103), and by subtyping publicly available data from metastatic samples (n=573) from external patient cohorts. The MetB subtype was associated with high tumor-cell proliferation, low androgen receptor activity, and poor prognosis in all cohorts, and provided independent prognostic information in addition to genetic aberrations.

Study 3: The miRNA profiles of 96 bone metastasis samples from Study 2 were examined using microarray analysis. Four sample clusters not obviously related to the MetA-C subtypes were observed. Expression levels of miRNA-375, however, were inversely related to MetB. MiRNA-375 overexpression in C4-2B resulted in a cellular switch of subtype, from being dominant MetB to dominant MetA. In parallel, reduced cell growth and signs of increased cell adhesion were observed.

In conclusion, altered miRNA profiles may contribute to progression of PC into bone metastasis, and to the development of different metastasis subtypes. The MetB subtype is associated with poor prognosis and low expression of miRNA-375. Therapy stratification based on the MetA-C subtypes should be considered in the future. Restoration of miRNA-375 in MetB tumors may offer a novel treatment option.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2023. p. 76
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2269
Keywords
Prostate cancer bone metastases, microRNA, metastatic subtypes, extracellular vesicles
National Category
Cancer and Oncology
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-215629 (URN)978-91-8070-168-6 (ISBN)978-91-8070-169-3 (ISBN)
Public defence
2023-11-17, Hörsal B, byggnad 1D, 9 tr, Tandläkarhögskolan, Norrlands Universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2023-10-27 Created: 2023-10-23 Last updated: 2023-10-23Bibliographically approved

Open Access in DiVA

No full text in DiVA

Authority records

Järemo, HelenaSemenas, JuliusHalin Bergström, SofiaThysell, ElinLundholm, MarieJosefsson, AndreasThellenberg-Karlsson, CamillaCrnalic, SeadBergh, AndersBrattsand, MariaWikström, Pernilla

Search in DiVA

By author/editor
Järemo, HelenaSemenas, JuliusHalin Bergström, SofiaThysell, ElinLundholm, MarieJosefsson, AndreasThellenberg-Karlsson, CamillaCrnalic, SeadBergh, AndersBrattsand, MariaWikström, Pernilla
By organisation
PathologyUrology and AndrologyWallenberg Centre for Molecular Medicine at Umeå University (WCMM)OncologyOrthopaedics
Cancer and Oncology

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 65 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf