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Järemo, H., Semenas, J., Halin Bergström, S., Lundholm, M., Thysell, E., Widmark, A., . . . Wikström, P. (2023). Investigating microRNA Profiles in Prostate Cancer Bone Metastases and Functional Effects of microRNA-23c and microRNA-4328. Cancers, 15(9), Article ID 2437.
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
Bovinder Ylitalo, E., Thysell, E., Landfors, M., Brattsand, M., Jernberg, E., Crnalic, S., . . . Wikström, P. (2021). A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer. Clinical Epigenetics, 13(1), Article ID 133.
Open this publication in new window or tab >>A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer
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2021 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 13, no 1, article id 133Article in journal (Refereed) Published
Abstract [en]

Background: Patients with metastatic prostate cancer (PC) are treated with androgen deprivation therapy (ADT) that initially reduces metastasis growth, but after some time lethal castration-resistant PC (CRPC) develops. A better understanding of the tumor biology in bone metastases is needed to guide further treatment developments. Subgroups of PC bone metastases based on transcriptome profiling have been previously identified by our research team, and specifically, heterogeneities related to androgen receptor (AR) activity have been described. Epigenetic alterations during PC progression remain elusive and this study aims to explore promoter gene methylation signatures in relation to gene expression and tumor AR activity.

Materials and methods: Genome-wide promoter-associated CpG methylation signatures of a total of 94 tumor samples, including paired non-malignant and malignant primary tumor areas originating from radical prostatectomy samples (n = 12), and bone metastasis samples of separate patients with hormone-naive (n = 14), short-term castrated (n = 4) or CRPC (n = 52) disease were analyzed using the Infinium Methylation EPIC arrays, along with gene expression analysis by Illumina Bead Chip arrays (n = 90). AR activity was defined from expression levels of genes associated with canonical AR activity.

Results: Integrated epigenome and transcriptome analysis identified pronounced hypermethylation in malignant compared to non-malignant areas of localized prostate tumors. Metastases showed an overall hypomethylation in relation to primary PC, including CpGs in the AR promoter accompanied with induction of AR mRNA levels. We identified a Methylation Classifier for Androgen receptor activity (MCA) signature, which separated metastases into two clusters (MCA positive/negative) related to tumor characteristics and patient prognosis. The MCA positive metastases showed low methylation levels of genes associated with canonical AR signaling and patients had a more favorable prognosis after ADT. In contrast, MCA negative patients had low AR activity associated with hypermethylation of AR-associated genes, and a worse prognosis after ADT.

Conclusions: A promoter methylation signature classifies PC bone metastases into two groups and predicts tumor AR activity and patient prognosis after ADT. The explanation for the methylation diversities observed during PC progression and their biological and clinical relevance need further exploration.

Place, publisher, year, edition, pages
BioMed Central, 2021
Keywords
Androgen receptor, DNA methylation, Gene expression, MetA, Metastasis, MetB, MetC, Prognosis, Prostate cancer, Subtypes
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-185893 (URN)10.1186/s13148-021-01119-0 (DOI)000670704300001 ()34193246 (PubMedID)2-s2.0-85109041809 (Scopus ID)
Available from: 2021-07-12 Created: 2021-07-12 Last updated: 2023-09-05Bibliographically approved
Lundwall, Å., Bovinder Ylitalo, E., Wikström, P. & Brattsand, M. (2021). Klk4t2 is a hormonally regulated transcript from the klk4 locus. International Journal of Molecular Sciences, 22(23), Article ID 13023.
Open this publication in new window or tab >>Klk4t2 is a hormonally regulated transcript from the klk4 locus
2021 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, no 23, article id 13023Article in journal (Refereed) Published
Abstract [en]

The human kallikrein-related peptidase 4 (KLK4) and the transcribed pseudogene KLKP1 are reported to be highly expressed in the prostate. When trying to clone transcripts of KLKP1, we partly failed. Instead, we identified an androgen-regulated transcript, KLK4T2, which appeared to be a splice variant of KLK4 that also contained exons of KLKP1. Expression analysis of KLK4, KLK4T2, and KLKP1 transcripts in prostate cancer cell lines showed high levels of KLKP1 transcripts in the nucleus and in unfractionated cell extract, whereas it was almost completely absent in the cytoplasmatic fraction. This was in contrast to KLK4 and KLK4T2, which displayed high to mod-erate levels in the cytoplasm. In patient cohorts we found significantly higher expression of both KLK4T2 and KLK4 in benign prostatic hyperplasia compared to both primary prostate cancer and bone metastasis. Analysis of tissue panels demonstrated the highest expression of KLK4T2 in the prostate, but in contrast to the classical KLK4, relatively high levels were also found in placenta. So far, the function of KLK4T2 is still to be explored, but the structure of the translation product indicated that it generates a 17.4 kDa intracellular protein with possible regulatory function.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
Bone metastasis, Kallikrein-related peptidases, KLK4, KLK4T2, KLKP1, Prostate cancer, Splice variant, Transcripts
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-190107 (URN)10.3390/ijms222313023 (DOI)000742962000001 ()2-s2.0-85120163078 (Scopus ID)
Funder
Cancerforskningsfonden i NorrlandSwedish Cancer Society, 2018/863Swedish Research Council, 2018-02594
Available from: 2021-12-10 Created: 2021-12-10 Last updated: 2023-09-05Bibliographically approved
Brattsand, M. (2020). Doxycycline at Low Concentrations Could Influence Your Experimental Results When Working With Prostate Cancer Cell Lines. Biomedical Journal of Scientific & Technical Research, 28(2), 21515-21519
Open this publication in new window or tab >>Doxycycline at Low Concentrations Could Influence Your Experimental Results When Working With Prostate Cancer Cell Lines
2020 (English)In: Biomedical Journal of Scientific & Technical Research, ISSN 2574-1241, Vol. 28, no 2, p. 21515-21519Article in journal (Refereed) Published
Abstract [en]

Doxycycline is a tetracycline derivate commonly used in various inducible expression systems to study the function of different proteins. In this study, we show that 22Rv1 and PC3, two different, commonly used prostate cancer cell lines are very sensitive to this antibiotic and addition of the drug at inductive concentrations can affect cells in ways that can be misinterpreted as effects from the protein studied. Therefore, proper controls are very important in order to avoid conclusions drawn by artifacts caused by experimental conditions.

Place, publisher, year, edition, pages
Biomedical Research Network, 2020
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-175770 (URN)10.26717/BJSTR.2020.28.004636 (DOI)
Available from: 2020-10-08 Created: 2020-10-08 Last updated: 2020-10-08Bibliographically approved
Bovinder Ylitalo, E., Thysell, E., Thellenberg-Karlsson, C., Lundholm, M., Widmark, A., Bergh, A., . . . Wikström, P. (2020). Marked response to cabazitaxel in prostate cancer xenografts expressing androgen receptor variant 7 and reversion of acquired resistance by anti-androgens. The Prostate, 80(2), 214-224
Open this publication in new window or tab >>Marked response to cabazitaxel in prostate cancer xenografts expressing androgen receptor variant 7 and reversion of acquired resistance by anti-androgens
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2020 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 80, no 2, p. 214-224Article in journal (Refereed) Published
Abstract [en]

Background: Taxane treatment may be a suitable therapeutic option for patients with castration‐resistant prostate cancer and high expression of constitutively active androgen receptor variants (AR‐Vs). The aim of the study was to compare the effects of cabazitaxel and androgen deprivation treatments in a prostate tumor xenograft model expressing high levels of constitutively active AR‐V7. Furthermore, mechanisms behind acquired cabazitaxel resistance were explored.

Methods: Mice were subcutaneously inoculated with 22Rv1 cells and treated with surgical castration (n = 7), abiraterone (n = 9), cabazitaxel (n = 6), castration plus abiraterone (n = 8), castration plus cabazitaxel (n = 11), or vehicle and/or sham operation (n = 23). Tumor growth was followed for about 2 months or to a volume of approximately 1000 mm3. Two cabazitaxel resistant cell lines; 22Rv1‐CabR1 and 22Rv1‐CabR2, were established from xenografts relapsing during cabazitaxel treatment. Differential gene expression between the cabazitaxel resistant and control 22Rv1 cells was examined by whole‐genome expression array analysis followed by immunoblotting, immunohistochemistry, and functional pathway analysis.

Results: Abiraterone treatment alone or in combination with surgical castration had no major effect on 22Rv1 tumor growth, while cabazitaxel significantly delayed and in some cases totally abolished 22Rv1 tumor growth on its own and in combination with surgical castration. The cabazitaxel resistant cell lines; 22Rv1‐CabR1 and 22Rv1‐CabR2, both showed upregulation of the ATP‐binding cassette sub‐family B member 1 (ABCB1) efflux pump. Treatment with ABCB1 inhibitor elacridar completely restored susceptibility to cabazitaxel, while treatment with AR‐antagonists bicalutamide and enzalutamide partly restored susceptibility to cabazitaxel in both cell lines. The cholesterol biosynthesis pathway was induced in the 22Rv1‐CabR2 cell line, which was confirmed by reduced sensitivity to simvastatin treatment.

Conclusions: Cabazitaxel efficiently inhibits prostate cancer growth despite the high expression of constitutively active AR‐V7. Acquired cabazitaxel resistance involving overexpression of efflux transporter ABCB1 can be reverted by bicalutamide or enzalutamide treatment, indicating the great clinical potential for combined treatment with cabazitaxel and anti‐androgens.

Place, publisher, year, edition, pages
John Wiley & Sons, 2020
Keywords
ABCB1, androgen receptor, cabazitaxel, cholesterol, prostate cancer, splice variant
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-167098 (URN)10.1002/pros.23935 (DOI)000500369300001 ()31799745 (PubMedID)2-s2.0-85076111685 (Scopus ID)
Funder
Swedish Cancer Society, CAN 2013/1324Swedish Cancer Society, CAN 2018/863Swedish Research Council, 2018-02594
Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2023-03-23Bibliographically approved
Chen, X., Leahy, D., Van Haeften, J., Hartfield, P., Prentis, P. J., van der Burg, C. A., . . . Harris, J. M. (2019). A Versatile and Robust Serine Protease Inhibitor Scaffold from Actinia tenebrosa. Marine Drugs, 17(12), Article ID 701.
Open this publication in new window or tab >>A Versatile and Robust Serine Protease Inhibitor Scaffold from Actinia tenebrosa
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2019 (English)In: Marine Drugs, E-ISSN 1660-3397, Vol. 17, no 12, article id 701Article in journal (Refereed) Published
Abstract [en]

Serine proteases play pivotal roles in normal physiology and a spectrum of patho-physiological processes. Accordingly, there is considerable interest in the discovery and design of potent serine protease inhibitors for therapeutic applications. This led to concerted efforts to discover versatile and robust molecular scaffolds for inhibitor design. This investigation is a bioprospecting study that aims to isolate and identify protease inhibitors from the cnidarian Actinia tenebrosa. The study isolated two Kunitz-type protease inhibitors with very similar sequences but quite divergent inhibitory potencies when assayed against bovine trypsin, chymostrypsin, and a selection of human sequence-related peptidases. Homology modeling and molecular dynamics simulations of these inhibitors in complex with their targets were carried out and, collectively, these methodologies enabled the definition of a versatile scaffold for inhibitor design. Thermal denaturation studies showed that the inhibitors were remarkably robust. To gain a fine-grained map of the residues responsible for this stability, we conducted in silico alanine scanning and quantified individual residue contributions to the inhibitor’s stability. Sequences of these inhibitors were then used to search for Kunitz homologs in an A. tenebrosa transcriptome library, resulting in the discovery of a further 14 related sequences. Consensus analysis of these variants identified a rich molecular diversity of Kunitz domains and expanded the palette of potential residue substitutions for rational inhibitor design using this domain.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
Actinia tenebrosa, kallikrein-related peptidases, Kunitz inhibitor, serine protease, mass spectrometry imaging, molecular dynamics simulation
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-167642 (URN)10.3390/md17120701 (DOI)000507340000053 ()31842369 (PubMedID)2-s2.0-85076293427 (Scopus ID)
Available from: 2020-02-03 Created: 2020-02-03 Last updated: 2024-07-04Bibliographically approved
Chen, X., Riley, B. T., de Veer, S. J., Hoke, D. E., Van Haeften, J., Leahy, D., . . . Harris, J. M. (2019). Potent, multi-target serine protease inhibition achieved by a simplified beta-sheet motif. PLOS ONE, 14(1), Article ID e0210842.
Open this publication in new window or tab >>Potent, multi-target serine protease inhibition achieved by a simplified beta-sheet motif
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2019 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 1, article id e0210842Article in journal (Refereed) Published
Abstract [en]

Engagement of an extended beta-sheet is a common substrate/inhibitor interaction at the active site of serine proteases and is an important feature of Laskowski mechanism inhibitors that present a substrate-like loop to a target protease. This loop is cleaved but subsequently relegated forming a stable inhibitor/protease complex. Laskowski inhibitors are ubiquitous in nature and are used extensively in serine protease inhibitor design. However, most studies concentrate on introducing new sidechain interactions rather than the direct contributions of the substrate-like beta-sheet to enzyme inhibition. Here we report the crystal structure of an simplified beta-sheet inhibitory motif within the Sunflower Trypsin Inhibitor (SFTI) in complex with trypsin. We show that the intramolecular hydrogen bond network of this SFTI variant (SFTI-TCTR) engages the inhibitor sidechains that would normally interact with a target protease, giving mainchain interactions a more prominent role in complex formation. Despite having reduced sidechain interactions, this SFTI variant is remarkably potent and inhibits a diverse range of serine proteases. Crystal structural analysis and molecular modelling of SFTI-TCTR complexes again indicates an interface dominated by beta-sheet interactions, highlighting the importance of this motif and the adaptability of SFTI as a scaffold for inhibitor design.

Place, publisher, year, edition, pages
Public Library Science, 2019
National Category
Medicinal Chemistry Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-156314 (URN)10.1371/journal.pone.0210842 (DOI)000456306400019 ()30668585 (PubMedID)2-s2.0-85060316770 (Scopus ID)
Available from: 2019-02-20 Created: 2019-02-20 Last updated: 2023-03-23Bibliographically approved
Haddada, M., Draoui, H., Deschamps, L., Walker, F., Delaunay, T., Brattsand, M., . . . Darmoul, D. (2018). Kallikrein-related peptidase 7 overexpression in melanoma cells modulates cell adhesion leading to a malignant phenotype. Biological chemistry (Print), 399(9), 1099-1105
Open this publication in new window or tab >>Kallikrein-related peptidase 7 overexpression in melanoma cells modulates cell adhesion leading to a malignant phenotype
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2018 (English)In: Biological chemistry (Print), ISSN 1431-6730, E-ISSN 1437-4315, Vol. 399, no 9, p. 1099-1105Article in journal (Refereed) Published
Abstract [en]

We recently reported that human melanoma cells, but not benign melanocytes, aberrantly express kallikrein-related peptidase 7 (KLK7). Here, we show a KLK7 overexpression-mediated decrease of cell adhesion to extracellular matrix binding proteins, associated with downregulation of alpha 5/beta 1/alpha v/beta 3 integrin expression. We also report an up-regulation of MCAM/CD146 and an increase in spheroid formation of these cells. Our results demonstrate that aberrant KLK7 expression leads to a switch to a more malignant phenotype suggesting a potential role of KLK7 in melanoma invasion. Thus, KLK7 may represent a biomarker for melanoma progression and may be a potential therapeutic target for melanoma.

Place, publisher, year, edition, pages
Walter de Gruyter, 2018
Keywords
E-cadherin, integrins, kallikrein-related peptidase 7, MCAM/CD146, melanoma, spheroid
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-151387 (URN)10.1515/hsz-2017-0339 (DOI)000441526200018 ()29498930 (PubMedID)2-s2.0-85043251579 (Scopus ID)
Available from: 2018-09-06 Created: 2018-09-06 Last updated: 2023-03-23Bibliographically approved
Brattsand, M. (2018). Kan KLK7 vara en användbar biomarkör för progression av melanom?. BestPractice Dermatologi, 9(25)
Open this publication in new window or tab >>Kan KLK7 vara en användbar biomarkör för progression av melanom?
2018 (Swedish)In: BestPractice Dermatologi, Vol. 9, no 25Article, review/survey (Other academic) Published
Place, publisher, year, edition, pages
Ballerup, Danmark: BestPractice ApS, 2018
National Category
Dermatology and Venereal Diseases
Research subject
Dermatology and Venerology
Identifiers
urn:nbn:se:umu:diva-154115 (URN)
Available from: 2018-12-12 Created: 2018-12-12 Last updated: 2022-04-19Bibliographically approved
Delaunay, T., Deschamps, L., Haddada, M., Walker, F., Soosaipillai, A., Soualmia, F., . . . Darmoul, D. (2017). Aberrant expression of kallikrein-related peptidase 7 is correlated with human melanoma aggressiveness by stimulating cell migration and invasion. Molecular Oncology, 11(10), 1330-1347
Open this publication in new window or tab >>Aberrant expression of kallikrein-related peptidase 7 is correlated with human melanoma aggressiveness by stimulating cell migration and invasion
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2017 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 11, no 10, p. 1330-1347Article in journal (Refereed) Published
Abstract [en]

Members of the tissue kallikrein-related peptidase (KLK) family not only regulate several important physiological functions, but aberrant expression has also been associated with various malignancies. Clinically, KLKs have been suggested as promising biomarkers for diagnosis and prognosis in many types of cancer. As of yet, expression of KLKs and their role in skin cancers are, however, poorly addressed. Malignant melanoma is an aggressive disease associated with poor prognosis. Hence, diagnostic biomarkers to monitor melanoma progression are needed. Herein, we demonstrate that although mRNA of several KLKs are aberrantly expressed in melanoma cell lines, only the KLK7 protein is highly secreted in vitro. In line with these findings, ectopic expression of KLK7 in human melanomas and its absence in benign nevi were demonstrated by immunohistochemistry in vivo. Interestingly, overexpression of KLK7 induced a significant reduction in melanoma cell proliferation and colony formation. Moreover, KLK7 overexpression triggered an increase in cell motility and invasion associated with decreased expression of E-cadherin and an upregulation of MCAM/CD146. Our results demonstrate, for the first time, that aberrant KLK7 expression leads to a switch from proliferative to invasive phenotype, suggesting a potential role of KLK7 in melanoma progression. Thus, we hypothesize that KLK7 may represent a potential biomarker for melanoma progression.

Keywords
E-cadherin, invasion, kallikrein-related peptidase 7, melanoma, migration, proliferation
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-142381 (URN)10.1002/1878-0261.12103 (DOI)000417440300002 ()28636767 (PubMedID)2-s2.0-85030229403 (Scopus ID)
Available from: 2017-11-29 Created: 2017-11-29 Last updated: 2023-03-24Bibliographically approved
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