Abstract
Background
Vitamin D deficiency is prevalent among the Indonesian population, particularly in individuals diagnosed with leukemia-lymphoma. The regulation of vitamin D metabolism is influenced by the expression of several enzymes, such as CYP2R1, CYP24A1, and the vitamin D receptor (VDR). This study aimed to scrutinize the gene expression profiles in both mRNA and protein levels of VDR, CYP2R1, and CYP24A1 in leukemia and lymphoma patients.
Method
The research was a cross-sectional study conducted at Cipto Mangunkusumo Hospital (RSCM) in Jakarta, Indonesia. The study included a total of 45 patients aged over 18 years old who have received a diagnosis of lymphoma or leukemia. Vitamin D status was measured by examining serum 25 (OH) D levels. The analysis of VDR, CYP2R1, and CYP24A1 mRNA expression utilized the qRT-PCR method, while protein levels were measured through the ELISA method.
Conclusion
The study revealed a noteworthy difference in VDR protein levels between men and women. The highest mean CYP24A1 protein levels were observed in the age group > 60 years. This study found a significant, moderately positive correlation between VDR protein levels and CYP24A1 protein levels in the male and vitamin D sufficiency groups. In addition, a significant positive correlation was found between VDR mRNA levels and CYP2R1 mRNA levels, VDR mRNA levels and CYP2R1 mRNA levels, and CYP2R1 mRNA levels and CYP24A1 mRNA levels. However, the expression of these genes does not correlate with the protein levels of its mRNA translation products in blood circulation.
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Data availability
The datasets used and/or analyzed during the current study are available in our institutionalized database and the Copy Right of this study has been deposited in the repository of Yarsi University, or please contact the corresponding author upon reasonable request.
References
BaekerBispo JA, Pinheiro PS, Kobetz EK (2020) Epidemiology and etiology of leukemia and lymphoma. Cold Spring Harb Perspect Med 10(6):a034819
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249
Thandra KC, Barsouk A, Saginala K, Padala SA, Barsouk A, Rawla P (2021) Epidemiology of non-Hodgkin’s lymphoma. Med Sci 9:1–5
Kulling PM, Olson KC, Olson TL, Feith DJ, Loughran TP (2017) Vitamin D in hematological disorders and malignancies. Eur J Haematol 98:187–197
Gupta D, Vashi PG, Trukova K, Lis CG, Lammersfeld CA (2011) Prevalence of serum vitamin D deficiency and insufficiency in cancer: review of the epidemiological literature. Exp Therap Med. 2:181–193
Pineda-Lancheros LE, Gálvez-Navas JM, Rojo-Tolosa S, Membrive-Jiménez C, Valverde-Merino MI, Martínez-Martínez F et al (2023) Polymorphisms in VDR, CYP27B1, CYP2R1, GC and CYP24A1 genes as biomarkers of survival in non-small cell lung cancer: a systematic review. Nutrients 15:1525
Rachman A, Rahmaniyah R, Khomeini A, Iriani A (2023) Impact of vitamin D deficiency in relation to the clinical outcomes of hospitalized COVID-19 patients. F1000Res 12:394
Martens PJ, Gysemans C, Verstuyf A, Mathieu C (2020) Vitamin d’s effect on immune function. Nutrients 12
Sîrbe C, Rednic S, Grama A, Pop TL (2022) An update on the effects of vitamin D on the immune system and autoimmune diseases. Int J Mol Sci 23:9784
Potre C, Borsi E, Potre O, Ionita I, Samfireag M, Costachescu D et al (2023) A systematic review assessing the impact of vitamin D levels on adult patients with lymphoid malignancies. Curr Oncol 30:4351–4364
Hohaus S, Tisi MC, Bellesi S, Maiolo E, Alma E, Tartaglia G et al (2018) Vitamin D deficiency and supplementation in patients with aggressive B-cell lymphomas treated with immunochemotherapy. Cancer Med 7(1):270–281
Norlin M, Wikvall K (2023) Enzymatic activation in vitamin D signaling—past, present and future. Arch Biochem Biophy 742:109639
Máčová L, Bičíková M (2021) Vitamin D: current challenges between the laboratory and clinical practice. Nutrients 13
Pilz S, Zittermann A, Trummer C, Theiler-Schwetz V, Lerchbaum E, Keppel MH et al (2019) Vitamin D testing and treatment: a narrative review of current evidence. Endocr Connect 8(2):R27-43
Cui A, Zhang T, Xiao P, Fan Z, Wang H, Zhuang Y (2023) Global and regional prevalence of vitamin D deficiency in population-based studies from 2000 to 2022: a pooled analysis of 7.9 million participants. Front Nutr 10:01–13
Nimitphong H, Holick MF (2013) Vitamin D status and sun exposure in Southeast Asia. Dermatoendocrinol 5(1):34–37
Octavius GS, Shakila A, Meliani M, Halim A (2023) Vitamin D deficiency is a public health emergency among Indonesian children and adolescents: a systematic review and meta-analysis of prevalence. Ann Pediatr Endocrinol Metab 28(1):10–19
Ma K, Xu W, Wang C, Li B, Su K, Li W (2017) Vitamin D deficiency is associated with a poor prognosis in advanced non-small cell lung cancer patients treated with platinum-based first-line chemotherapy. Cancer Biomark 18(3):297–303
Wang W, Li G, He X, Gao J, Wang R, Wang Y et al (2015) Serum 25-hydroxyvitamin D levels and prognosis in hematological malignancies: A systematic review and meta-analysis. Cell Physiol Biochem 35:1999–2005
Seraphin G, Rieger S, Hewison M, Capobianco E, Lisse TS (2023) The impact of vitamin D on cancer: a mini review. J Steroid Biochem Mol Biol 231:106308
Bao L, Wang YT, Lu MQ, Chu B, Shi L, Gao S et al (2023) Vitamin D deficiency linked to abnormal bone and lipid metabolism predicts high-risk multiple myeloma with poorer prognosis. Front Endocrinol. https://doi.org/10.3389/fendo.2023.1157969
Jeon SM, Shin EA (2018) Exploring vitamin D metabolism and function in cancer. Exp Mol Med 50:1–14
Sadeghi H, Kamaliyan Z, Mohseni R, Sahebi U, Nazemalhosseini-Mojarad E, Aghaei N et al (2021) Dysregulation of vitamin D synthesis pathway genes in colorectal cancer: a case-control study. J Clin Lab Anal. https://doi.org/10.1002/jcla.23617
Pludowski P, Takacs I, Boyanov M, Belaya Z, Diaconu CC, Mokhort T, et al. (2022) Clinical practice in the prevention, diagnosis and treatment of vitamin d deficiency: a central and Eastern European expert consensus statement. Nutrients 14
Tantri AR, Soenarto RF, Firdaus R, Theresia S, Anakotta V (2022) Low incidence of vitamin D levels deficiency in anesthesiology residents: a cross-sectional, retrospective study. Bali J Anesthesiol 6(4):210–214
Rachman A, Iriani A, Priantono D, Rumondor BB, Betsy R, Juanputra S (2022) The correlation between serum 25-hydroxy-vitamin D levels and anti-SARS-CoV-2 S-RBD IgG and neutralizing antibody levels among cancer patients receiving COVID-19 vaccines. Front Nutr 13:9
Voltan G, Cannito M, Ferrarese M, Ceccato F, Camozzi V (2023) Vitamin D: an overview of gene regulation, ranging from metabolism to genomic effects. Genes 14:1691
Carlberg C (2022) Vitamin D and its target genes. Nutrients14
Rochel N (2022) Vitamin D and its receptor from a structural perspective. Nutrients 14
Shirvani SS, Nouri M, Sakhinia E, Babaloo Z, Jadideslam G, Shahriar A et al (2019) The expression and methylation status of vitamin D receptor gene in Behcet’s disease. Immun Inflamm Dis. 7(4):308–317
Apprato G, Fiz C, Fusano I, Bergandi L, Silvagno F (2020) Natural epigenetic modulators of vitamin D receptor. Appl Sci 10:4096
Fronczek M, Strzelczyk JK, Biernacki K, Salatino S, Osadnik T, Ostrowska Z (2021) New variants of the cytochrome p450 2r1 (Cyp2r1) gene in individuals with severe vitamin d-activating enzyme 25(OH)D deficiency. Biomolecules 11(12):1867
Duan L, Xue Z, Ji H, Zhang D, Wang Y (2018) Effects of CYP2R1 gene variants on vitamin D levels and status: a systematic review and meta-analysis. Gene 678:361–369
Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G (2016) Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev 96:365–408
Gleba JJ, Kłopotowska D, Banach J, Mielko KA, Turlej E, Maciejewska M et al (2022) Micro-RNAs in response to active forms of vitamin D3 in human leukemia and lymphoma cells. Int J Mol Sci 23(9):5019
Campbell MJ, Trump DL (2017) Vitamin D receptor signaling and cancer. Endocrinol Metabol Clin North Am. 46:1009–1038
Fetahu IS, Höbaus J, Kállay E (2014) Vitamin D and the epigenome. APR Front Physiol 5
Forouhari A, Heidari-Beni M, Veisi S, Poursafa P, Kelishadi R (2023) Effect of epigenetics on vitamin D levels: a systematic review until December 2020. Arch Public Health. https://doi.org/10.1186/s13690-023-01122-2
Afshan FU, Masood A, Nissar B, Chowdri NA, Naykoo NA, Majid M et al (2021) Promoter hypermethylation regulates vitamin D receptor (VDR) expression in colorectal cancer—a study from Kashmir valley. Cancer Genet 1(252–253):96–106
Paubelle E, Zylbersztejn F, Maciel TT, Carvalho C, Mupo A, Cheok M et al (2020) Vitamin D receptor controls cell stemness in acute myeloid leukemia and in normal bone marrow. Cell Rep 30(3):739-754.e4
Nowak U, Janik S, Marchwicka A, Łaszkiewicz A, Jakuszak A, Cebrat M et al (2020) Investigating the role of methylation in silencing of VDR gene expression in normal cells during hematopoiesis and in their leukemic counterparts. Cells 9(9):1991
Zhu H, Wang X, Shi H, Su S, Harshfield GA, Gutin B et al (2013) A genome-wide methylation study of severe vitamin d deficiency in African American adolescents. J Pediatr 162(5):1004
Varadharajan A, Sibin MK, Athira SV, Ghosh AK, Misra P (2023) Correlation of CYP2R1 gene promoter methylation with circulating vitamin D levels among healthy adults. Indian J Med Res 158(2):197–200
Singh T, Adams BD (2017) The regulatory role of miRNAs on VDR in breast cancer. Transcription 8:232–241
Saleh RO, Al-Ouqaili MTS, Ali E, Alhajlah S, Kareem AH, Shakir MN et al (2024) lncRNA-microRNA axis in cancer drug resistance: particular focus on signaling pathways. Med Oncol. https://doi.org/10.1007/s12032-023-02263-8
Mohri T, Nakajima M, Takagi S, Komagata S, Yokoi T (2009) MicroRNA regulates human vitamin D receptor. Int J Cancer 125(6):1328–1333
Komagata S, Nakajima M, Takagi S, Mohri T, Taniya T, Yokoi T (2009) Human CYP24 catalyzing the inactivation of calcitriol is post-transcriptionally regulated by miR-125b. Mol Pharmacol 76(4):702–709
Kanaan BA, Al-Ouqaili MTS, Murshid RM (2023) Cytogenetic screening of chromosomal abnormalities and genetic analysis of FSH receptor Ala307Thr and Ser680Asn genes in amenorrheic patients. PeerJ 11:e15267
Linowiecka K, Wolnicka-Głubisz A, Brożyna AA (2021) Vitamin D endocrine system in breast cancer. Acta Biochim Pol 68(4):489–497
Johnson AD, Zhang Y, Papp AC, Pinsonneault JK, Lim JE, Saffen D et al (2008) Polymorphisms affecting gene transcription and mRNA processing in pharmacogenetic candidate genes: Detection through allelic expression imbalance in human target tissues. Pharmacogenet Genomics 18(9):781–791
Usategui-Martín R, De Luis-Román DA, Fernández-Gómez JM, Ruiz-Mambrilla M, Pérez-Castrillón JL (2022) Vitamin D receptor (VDR) gene polymorphisms modify the response to vitamin D supplementation: a systematic review and meta-analysis. Nutrients 14(2):360
Rahman KL, Akhter QS, Rahman MS, Rahman R, Sami SR, Mukta FY et al (2021) Genetic variations of CYP2R1 (rs10741657) in Bangladeshi adults with low serum 25(OH)D level—a pilot study. PLoS ONE 16:e0260298
Tomei S, Singh P, Mathew R, Mattei V, Garand M, Alwakeel M et al (2020) The role of polymorphisms in vitamin d-related genes in response to vitamin d supplementation. Nutrients 12(9):1–16
Wang Y, Han H, Wang J, Shen F, Yu F, Wang L et al (2019) Polymorphisms in CYP2R1 gene associated with serum vitamin D levels and status in a Chinese rural population. Biomed Environ Sci 32:550–553
Krasniqi E, Boshnjaku A, Wagner KH, Wessner B (2021) Association between polymorphisms in vitamin d pathway-related genes, vitamin d status, muscle mass and function: a systematic review. Nutrients 13(9):3109
Goldstein I, Rivlin N, Shoshana O, Ezra O, Madar S, Goldfinger N et al (2013) Chemotherapeutic agents induce the expression and activity of their clearing enzyme CYP3a4 by activating p53. Carcinogenesis 34(1):190–198
Acknowledgements
We would like to thank the following hospital management: Yarsi Hospital, and Cipto Mangunkusumo National General Hospital.
Funding
This research was funded by the Rumah Program Organization of Health National Research and Innovation Agency (BRIN), Grant number: B-231/III.9/PR.03.08/1/2023.
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AI, AR, and MFIN performed study concept and development of methodology; AI, MFIN, RKG, and AT performed validation; AR, AI, and RKG provided resource and investigation; AI, RKG, AT, and MKF provided data curation and performed formal analysis; AR, AI, RKG, and MKF performed writing original draft preparations; AI, MKF, and MFIN performed writing, review and editing of the paper; AI and MFIN provided supervision; MFIN performed project administration and founding acquisition. All authors have read and agreed to the published version of the manuscript.
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This study has received ethical approval from the Ethics Committee of the Faculty of Medicine Yarsi University No: 030/KEP-UY/EA.20/II/2023. This study was conducted following the declaration of Helsinki. Moreover, informed consent forms were duly signed by all participants.
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Iriani, A., Rachman, A., Fatina, M.K. et al. Gene expression profiling of vitamin D metabolism enzymes in leukemia and lymphoma patients: molecular aspect interplay of VDR, CYP2R1, and CYP24A1. Mol Biol Rep 51, 526 (2024). https://doi.org/10.1007/s11033-024-09432-6
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DOI: https://doi.org/10.1007/s11033-024-09432-6