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Differential expression of protein disulfide-isomerase A3 isoforms, PDIA3 and PDIA3N, in human prostate cancer cell lines representing different stages of prostate cancer
Jönköping University, School of Health and Welfare, HHJ. Biomedical Platform.ORCID iD: 0000-0002-0045-2133
Jönköping University, School of Health and Welfare, HHJ, Dep. of Natural Science and Biomedicine. Jönköping University, School of Health and Welfare, HHJ. Biomedical Platform.
Department of Biomedicine, School of Health Sciences, University of Skövde, Skövde, Sweden.
Jönköping University, School of Health and Welfare, HHJ, Dep. of Natural Science and Biomedicine. Jönköping University, School of Health and Welfare, HHJ. Biomedical Platform.ORCID iD: 0000-0002-9819-0468
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2021 (English)In: Molecular Biology Reports, ISSN 0301-4851, E-ISSN 1573-4978, Vol. 48, p. 2429-2436Article in journal (Refereed) Published
Abstract [en]

Prostate cancer (PCa) is a highly heterogeneous and unpredictable progressive disease. Sensitivity of PCa cells to androgens play a central role in tumor aggressiveness but biomarkers with high sensitivity and specificity that follow the progression of the disease has not yet been verified. The vitamin D endocrine system and its receptors, the Vitamin D Receptor (VDR) and the Protein Disulfide-Isomerase A3 (PDIA3), are related to anti-tumoral effects as well as carcinogenesis and have therefore been suggested as potential candidates for the prevention and therapy of several cancer forms, including PCa. In this study, we evaluated the mRNA expression of VDR and PDIA3 involved in vitamin D signaling in cell lines representing different stages of PCa (PNT2, P4E6, LNCaP, DU145 and PC3). This study further aimed to evaluate vitamin D receptors and their isoforms as potential markers for clinical diagnosis of PCa. A novel transcript isoform of PDIA3 (PDIA3N) was identified and found to be expressed in all PCa cell lines analyzed. Androgen-independent cell lines showed a higher mRNA expression ratio between PDIA3N/PDIA3 contrary to androgen-dependent cell lines that showed a lower mRNA expression ratio between PDIA3N/PDIA3. The structure of PDIA3N differed from PDIA3. PDIA3N was found to be a N-truncated isoform of PDIA3 and differences in protein structure suggests an altered protein function i.e. cell location, thioredoxin activity and affinity for 1,25(OH)2D3. Collectively, PDIA3 transcript isoforms, the ratio between PDIA3N/PDIA3 and especially PDIA3N, are proposed as candidate markers for future studies with different stages of PCa progression.

Place, publisher, year, edition, pages
Springer, 2021. Vol. 48, p. 2429-2436
Keywords [en]
Androgen dependency, PDIA3, PDIA3N, Prostate cancer, VDR, Vitamin D
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:hj:diva-52111DOI: 10.1007/s11033-021-06277-1ISI: 000632300000004PubMedID: 33761087Scopus ID: 2-s2.0-85103162678Local ID: HOA;;731562OAI: oai:DiVA.org:hj-52111DiVA, id: diva2:1540467
Available from: 2021-03-29 Created: 2021-03-29 Last updated: 2022-03-07Bibliographically approved
In thesis
1. Exploring vitamin D and steroid hormone receptors – from healthy elderly to prostate cancer cells
Open this publication in new window or tab >>Exploring vitamin D and steroid hormone receptors – from healthy elderly to prostate cancer cells
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The genetic background together with environmental factors and lifestyle are key contributors to the health of an individual. Genetic background is inherited and irreversible unless mutations occur. However, lifestyle habits (i.e., diet, stress, physical activity, smoking, and alcohol consumption) are modifiable factors that contribute to health or disease by affecting methylation of DNA, which regulates transcription of genes.

One of the most relevant lifestyle habits for health is maintaining adequate vitamin D levels in the body as vitamin D promotes calcium and phosphate absorption, supports the nervous and immune system function, and protects bone and muscle structure. Extreme low levels of vitamin D, vitamin D deficiency, has become a global public health concern, especially in the elderly population as vitamin D deficiency can lead to several health problems such as bone fracture, decreased muscle strength, cardiovascular and autoimmune diseases, depression, and breast, pancreatic, and prostate cancer.

Prostate cancer is an uncontrolled growth of cells within the prostate gland in the male reproductive system. Human prostate carcinomas are sensitive to androgens, and hormonal ablation therapy gives a temporary remission, followed by a relapse to an androgen-insensitive state. This indicates that steroid hormones, especially androgens, play a significant role in human prostatic carcinogenesis. The molecular effect of vitamin D as a steroid hormone and which steroid hormone receptor (SHR) mediates this effect are not fully understood.

This research project aims to increase our knowledge about SHRs, primarily the vitamin D receptors, in both health and disease, focusing on genomic, epigenomic, and transcriptomic perspectives in healthy elderly individuals and prostate cancer cells.

The results from the studies in this thesis could help us understand the importance of a healthy lifestyle, which includes vitamin D for health, where we found specific methylation markers involved in the down-regulation of cancer pathways that are associated with high physical activity and vitamin D supplementation. We have further confirmed that SHRs rarely work in isolation but rather as a crosstalk at the genomic level to regulate their transcription. Hopefully, this will help clarify the modulation of transcriptional responses in SHRs and explain the development of steroid hormone-dependent cancers such as prostate cancer. Last, but not least, we revealed that genetic and transcriptional markers are associated with the putative vitamin D receptor the protein disulfide isomerase family A member 3 (PDIA3). The genetic markers were detected in a healthy elderly population under vitamin D supplementation. The transcriptional markers, PDIA3, and a novel discovered isoform of PDIA3 (PDIA3N) were related to the androgen and cancer stage of prostate cancer cells and therefore are proposed as candidate markers for clinical diagnosis of prostate cancer.

Altogether, these findings support the relevance of studying vitamin D and steroid hormone receptors, especially the PDIA3 receptor, to understand some of the factors related to healthy aging and the etiology and progression of prostate cancer.

Place, publisher, year, edition, pages
Jönköping: Jönköping University, School of Health and Welfare, 2022. p. 89
Series
Hälsohögskolans avhandlingsserie, ISSN 1654-3602 ; 111
Keywords
vitamin D, steroid hormone receptors, lifestyle, methylation, SNPs, healthy elderly, prostate cancer cells, crosstalk, PDIA3
National Category
Cancer and Oncology Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:hj:diva-56001 (URN)978-91-88669-10-0 (ISBN)
Public defence
2022-04-07, Forum Humanum, School of Health and Welfare, Jönköping, 13:00 (English)
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Supervisors
Available from: 2022-03-07 Created: 2022-03-07 Last updated: 2022-08-16Bibliographically approved

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Diaz Cruz, Maria AraceliKarlsson, SandraFaresjö, MariaLund, Dan

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