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MicroRNA expression profiles in prostate cancer bone metastases: functional effects of microRNA-23c, -375, and -4328
Umeå University, Faculty of Medicine, Department of Medical Biosciences. Umeå University.ORCID iD: 0009-0002-0666-8952
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 [en]
Prostate cancer bone metastases, microRNA, metastatic subtypes, extracellular vesicles
National Category
Cancer and Oncology
Research subject
Pathology
Identifiers
URN: urn:nbn:se:umu:diva-215629ISBN: 978-91-8070-168-6 (print)ISBN: 978-91-8070-169-3 (electronic)OAI: oai:DiVA.org:umu-215629DiVA, id: diva2:1806591
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
List of papers
1. Investigating microRNA Profiles in Prostate Cancer Bone Metastases and Functional Effects of microRNA-23c and microRNA-4328
Open this publication in new window or tab >>Investigating microRNA Profiles in Prostate Cancer Bone Metastases and Functional Effects of microRNA-23c and microRNA-4328
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2023 (English)In: Cancers, ISSN 2072-6694, Vol. 15, no 9, article id 2437Article in journal (Refereed) Published
Abstract [en]

MicroRNAs (miRNAs) are aberrantly expressed in prostate cancer (PC), but comprehensive knowledge about their levels and function in metastatic PC is lacking. Here, we explored the differential expression of miRNA profiles during PC progression to bone metastasis, and further focused on the downregulation of miRNA-23c and -4328 and their impact on PC growth in experimental models. Using microarray screening, the levels of 1510 miRNAs were compared between bone metastases (n = 14), localized PC (n = 7) and benign prostate tissue (n = 7). Differentially expressed miRNAs (n = 4 increased and n = 75 decreased, p < 0.05) were identified, of which miRNA-1, -23c, -143-3p, -143-5p, -145-3p, -205-5p, -221-3p, -222-3p and -4328 showed consistent downregulation during disease progression (benign > localized PC > bone metastases). The downregulation of miRNA-23c and -4328 was confirmed by reverse transcription and quantitative polymerase chain reaction analysis of 67 metastasis, 12 localized PC and 12 benign prostate tissue samples. The stable overexpression of miRNA-23c and -4328 in the 22Rv1 and PC-3 cell lines resulted in reduced PC cell growth in vitro, and in the secretion of high levels of miRNA-23c (but not -4328) in extracellular vesicles. However, no tumor suppressive effects were observed from miRNA-23c overexpression in PC-3 cells subcutaneously grown in mice. In conclusion, bone metastases display a profound reduction of miRNA levels compared to localized PC and benign disease. The downregulation of those miRNAs, including miRNA-23c and -4328, may lead to a loss of tumor suppressive effects and provide biomarker and therapeutic possibilities that deserve to be further explored.

Place, publisher, year, edition, pages
MDPI, 2023
Keywords
blood vessels, bone metastasis, extracellular vesicles, microarray, microRNA-23c, microRNA-4328, proliferation, prostate cancer, proteomics
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-209116 (URN)10.3390/cancers15092437 (DOI)000986796000001 ()2-s2.0-85159230526 (Scopus ID)
Funder
Swedish Research Council, 2022-00946Swedish Cancer Society, 21-1856Swedish Foundation for Strategic Research, RB13-0119Cancerforskningsfonden i Norrland, AMP 21-1061Prostatacancerförbundet
Available from: 2023-06-07 Created: 2023-06-07 Last updated: 2023-10-23Bibliographically approved
2. Clinical and biological relevance of the transcriptomic-based prostate cancer metastasis subtypes MetA-C
Open this publication in new window or tab >>Clinical and biological relevance of the transcriptomic-based prostate cancer metastasis subtypes MetA-C
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2022 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, no 4Article in journal (Refereed) Published
Abstract [en]

To improve treatment of metastatic prostate cancer, the biology of metastases needs to be understood. We recently described three subtypes of prostate cancer bone metastases (MetA-C), based on differential gene expression. The aim of this study was to verify the clinical relevance of these subtypes, and to explore their biology and relations to genetic drivers. Freshly-frozen metastasis samples were obtained as hormone-naive (n=17), short-term castrated (n=21) or castration resistant (n=65) from a total of 67 patients. Previously published sequencing data from 573 metastasis samples was also analyzed. Through transcriptome profiling and sample classification based on a set of predefined MetA-C-differentiating genes, we found that most metastases were heterogeneous for the MetA-C subtypes. Overall, MetA was the most common subtype, while MetB was significantly enriched in castration-resistant samples and in liver metastases, and consistently associated with poor prognosis. By gene set enrichment analysis, the phenotype of MetA was described by high androgen response, protein secretion and adipogenesis, MetB by high cell cycle activity and DNA repair, and MetC by epithelial-to-mesenchymal transition and inflammation. The MetB subtype demonstrated single-nucleotide variants of RB transcriptional corepressor 1 (RB1) and loss of 21 genes at chromosome 13, including RB1, but provided independent prognostic value to those genetic aberrations. In conclusion, a distinct set of gene transcripts can be used to classify prostate cancer metastases into the subtypes MetA-C. The MetA-C subtypes show diverse biology, organ tropism and prognosis. The MetA-C classification may be used independently, or in combination with genetic markers, primarily to identify MetB patients in need of complementary therapy to conventional androgen-receptor-targeting treatments.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
MetA-C, Metastasis, Prognosis, Prostate cancer, Subtypes, Transcriptomic
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-190463 (URN)10.1002/1878-0261.13158 (DOI)000734478400001 ()34889043 (PubMedID)2-s2.0-85121666619 (Scopus ID)
Available from: 2021-12-16 Created: 2021-12-16 Last updated: 2023-10-23Bibliographically approved
3. The microRNA landscape of prostate cancer bone metastases and the role of miRNA-375 in modulating phenotypic characteristics of metastatic cells
Open this publication in new window or tab >>The microRNA landscape of prostate cancer bone metastases and the role of miRNA-375 in modulating phenotypic characteristics of metastatic cells
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Research subject
Pathology; Pathology
Identifiers
urn:nbn:se:umu:diva-215545 (URN)
Available from: 2023-10-23 Created: 2023-10-23 Last updated: 2023-10-23

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