| 1. |
- Diaz Cruz, Maria Araceli, et al.
(författare)
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Characterization of methylation patterns associated with lifestyle factors and vitamin D supplementation in a healthy elderly cohort from Southwest Sweden
- 2022
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Ingår i: Scientific Reports. - : Nature Portfolio. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Numerous studies have shown that lifestyle factors, such as regular physical activity and vitamin D intake, may remarkably improve overall health and mental wellbeing. This is especially important in older adults whose vitamin D deficiency occurs with a high prevalence. This study aimed to examine the influence of lifestyle and vitamin D on global DNA methylation patterns in an elderly cohort in Southwest of Sweden. We also sought to examine the methylation levels of specific genes involved in vitamin D's molecular and metabolic activated pathways. We performed a genome wide methylation analysis, using Illumina Infinium DNA Methylation EPIC 850kBeadChip array, on 277 healthy individuals from Southwest Sweden at the age of 70-95. The study participants also answered queries on lifestyle, vitamin intake, heart medication, and estimated health. Vitamin D intake did not in general affect methylation patterns, which is in concert with other studies. However, when comparing the group of individuals taking vitamin supplements, including vitamin D, with those not taking supplements, a difference in methylation in the solute carrier family 25 (SCL25A24) gene was found. This confirms a previous finding, where changes in expression of SLC25A24 were associated with vitamin D treatment in human monocytes. The combination of vitamin D intake and high physical activity increased methylation of genes linked to regulation of vitamin D receptor pathway, the Wnt pathway and general cancer processes. To our knowledge, this is the first study detecting epigenetic markers associated with the combined effects of vitamin D supplementation and high physical activity. These results deserve to be further investigated in an extended, interventional study cohort, where also the levels of 25(OH)D3 can be monitored.
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| 2. |
- Diaz Cruz, Maria Araceli, et al.
(författare)
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Cis-regulatory elements in conserved non-coding sequences of nuclear receptor genes indicate for crosstalk between endocrine systems
- 2021
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Ingår i: Open Medicine (Poland). - : De Gruyter Open. - 2391-5463. ; 16:1, s. 640-650
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Tidskriftsartikel (refereegranskat)abstract
- Nuclear receptors (NRs) are ligand-activated transcription factors that regulate gene expression when bound to specific DNA sequences. Crosstalk between steroid NR systems has been studied for understanding the development of hormone-driven cancers but not to an extent at a genetic level. This study aimed to investigate crosstalk between steroid NRs in conserved intron and exon sequences, with a focus on steroid NRs involved in prostate cancer etiology. For this purpose, we evaluated conserved intron and exon sequences among all 49 members of the NR Superfamily (NRS) and their relevance as regulatory sequences and NR-binding sequences. Sequence conservation was found to be higher in the first intron (35%), when compared with downstream introns. Seventy-nine percent of the conserved regions in the NRS contained putative transcription factor binding sites (TFBS) and a large fraction of these sequences contained splicing sites (SS). Analysis of transcription factors binding to putative intronic and exonic TFBS revealed that 5 and 16%, respectively, were NRs. The present study suggests crosstalk between steroid NRs, e.g., vitamin D, estrogen, progesterone, and retinoic acid endocrine systems, through cis-regulatory elements in conserved sequences of introns and exons. This investigation gives evidence for crosstalk between steroid hormones and contributes to novel targets for steroid NR regulation.
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| 3. |
- Diaz Cruz, Maria Araceli, et al.
(författare)
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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
- 2021
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Ingår i: Molecular Biology Reports. - : Springer. - 0301-4851 .- 1573-4978. ; 48:3, s. 2429-2436
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Diaz Cruz, Maria Araceli
(författare)
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Exploring vitamin D and steroid hormone receptors – from healthy elderly to prostate cancer cells
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 5. |
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| 6. |
- Karlsson, Sandra, et al.
(författare)
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Inhibition of CYP27B1 and CYP24 Increases the Anti-proliferative Effects of 25-Hydroxyvitamin D 3 in LNCaP Cells
- 2021
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Ingår i: Anticancer Research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 41:10, s. 4733-4740
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aim: Growing evidence suggests that vitamin D3 exerts anticancer effects. The present study aimed to evaluate 25-hydroxyvitamin D3(25(OH)D3) as a potential endocrine factor regulating proliferation and vitamin D receptor expression in LNCaP prostate cancer cells. Materials and Methods: Cell counting after treatment was utilized to assess the effect of 25(OH)D3on cell proliferation. Changes in mRNA expression of the vitamin D receptors, VDR and PDIA3, were evaluated using droplet digital polymerase chain reaction (ddPCR). Results: 25(OH)D3inhibited cell proliferation in a dose- and time-dependent manner. The inhibitory effect of 25(OH)D3on cell proliferation was potentiated after inhibition of CYP17B1 and CYP24 by genistein, preventing further metabolism of 25(OH)D3to 1,25-dihydroxyvitamin D3(1,25(OH)2D3) and 24,25-dihydroxyvitamin D3(24,25(OH)2D3). Expression of PDIA3 and VDR mRNA increased after treatment with 25(OH)D3, whereas the ratio between PDIA3 and VDR mRNA remained unchanged. Conclusion: 25(OH)D3has a direct inhibitory effect on cell proliferation, which is enhanced and accelerated when the metabolism of 25(OH)D3to 1,25(OH)2D3and 24,25(OH)2D3was inhibited by the CYP17B1 and CYP24 inhibitor genistein. Furthermore, treatment with 25(OH)D3increased receptor transcript expression, suggesting an increased VDR stability and sensibility of the treated cells.
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