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BMC Cancer
Published in: BMC Cancer 1/2012

Open Access 01-12-2012 | Research article

Vitamin D3receptor is highly expressed in Hodgkin’s lymphoma

Authors: Christoph Renné, Alexander H Benz, Martin L Hansmann

Published in: BMC Cancer | Issue 1/2012

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Abstract

Background

Hodgkin lymphoma (HL) is one of the most frequent lymphoma in the western world. Despite a good overall prognosis, some patients suffer relapsing tumors which are difficult to cure. Over a long period Vitamin D has been shown to be a potential treatment for cancer. Vitamin D acts via the vitamin D receptor, a nuclear receptor, acting as an inducible transcription factor. We aimed to investigate the expression of vitamin D receptor as a possible diagnostic marker and potential therapeutic target in HL as well as in B-cell derived non-Hodgkin lymphoma (B-NHL).

Methods

We used a panel of 193 formalin fixed tissues of lymphoma cases consisting of 55 cases of HL and 138 cases on several B-NHL entities.

Results

Vitamin D receptor is strongly expressed in tumor cells of HL, regardless of the sub entity with an overall positivity of 80% of all HL cases. In contrast, only about 17% of the analyzed origin-NHL showed positivity for vitamin D receptor. The detection of nuclear localization of vitamin D receptor in the tumor cells of HL suggests activated status of the vitamin D receptor.

Conclusions

Our study suggests VDR as a specific marker for tumor cells of HL, but not of B-NHL subtypes. Further, the observed nuclear localization suggests an activated receptor status in tumor cells of HL. Further investigations of mutational status and functional studies may shed some light in functional relevance of vitamin D receptor signaling in HL.
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Literature
1.
WHO Classifination of Tumors of the Haematopoetic and Lymphoid Tissues. Edited by: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. 2008, Lyon, France: International Agency for Research on Cancer (IARC)
2.
Braeuninger A, Kuppers R, Strickler JG, Wacker HH, Rajewsky K, Hansmann ML: Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells. Proc Natl Acad Sci U S A. 1997, 94 (17): 9337-9342. 10.1073/pnas.94.17.9337.CrossRefPubMedPubMedCentral
3.
Kuppers R, Rajewsky K, Zhao M, Simons G, Laumann R, Fischer R, Hansmann ML: Hodgkin disease: Hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development. Proc Natl Acad Sci U S A. 1994, 91 (23): 10962-10966. 10.1073/pnas.91.23.10962.CrossRefPubMedPubMedCentral
4.
Willenbrock K, Ichinohasama R, Kadin ME, Miura I, Terui T, Meguro K, Fukuhara O, DeCoteau JF, Hansmann ML: T-cell variant of classical Hodgkin's lymphoma with nodal and cutaneous manifestations demonstrated by single-cell polymerase chain reaction. Laboratory investigation; a journal of technical methods and pathology. 2002, 82 (9)): 1103-1109.CrossRefPubMed
5.
Schwering I, Brauninger A, Klein U, Jungnickel B, Tinguely M, Diehl V, Hansmann ML, Dalla-Favera R, Rajewsky K, Kuppers R: Loss of the B-lineage-specific gene expression program in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood. 2003, 101 (4): 1505-1512. 10.1182/blood-2002-03-0839.CrossRefPubMed
6.
Joos S, Menz CK, Wrobel G, Siebert R, Gesk S, Ohl S, Mechtersheimer G, Trumper L, Moller P, Lichter P, et al: Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2. Blood. 2002, 99 (4): 1381-1387. 10.1182/blood.V99.4.1381.CrossRefPubMed
7.
Weber-Matthiesen K, Deerberg J, Poetsch M, Grote W, Schlegelberger B: Numerical chromosome aberrations are present within the CD30+ Hodgkin and Reed-Sternberg cells in 100% of analyzed cases of Hodgkin's disease. Blood. 1995, 86 (4): 1464-1468.PubMed
8.
Cabannes E, Khan G, Aillet F, Jarrett RF, Hay RT: Mutations in the IkBa gene in Hodgkin's disease suggest a tumour suppressor role for IkappaBalpha. Oncogene. 1999, 18 (20): 3063-3070. 10.1038/sj.onc.1202893.CrossRefPubMed
9.
Emmerich F, Meiser M, Hummel M, Demel G, Foss HD, Jundt F, Mathas S, Krappmann D, Scheidereit C, Stein H, et al: Overexpression of I kappa B alpha without inhibition of NF-kappaB activity and mutations in the I kappa B alpha gene in Reed-Sternberg cells. Blood. 1999, 94 (9): 3129-3134.PubMed
10.
Emmerich F, Theurich S, Hummel M, Haeffker A, Vry MS, Dohner K, Bommert K, Stein H, Dorken B: Inactivating I kappa B epsilon mutations in Hodgkin/Reed-Sternberg cells. J Pathol. 2003, 201 (3): 413-420. 10.1002/path.1454.CrossRefPubMed
11.
Jungnickel B, Staratschek-Jox A, Brauninger A, Spieker T, Wolf J, Diehl V, Hansmann ML, Rajewsky K, Kuppers R: Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in Hodgkin's lymphoma. J Exp Med. 2000, 191 (2): 395-402. 10.1084/jem.191.2.395.CrossRefPubMedPubMedCentral
12.
Kuppers R: B cells under influence: transformation of B cells by Epstein-Barr virus. Nature reviews. 2003, 3 (10): 801-812. 10.1038/nri1201.PubMed
13.
Brauninger A, Schmitz R, Bechtel D, Renne C, Hansmann ML, Kuppers R: Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma. Int J Cancer. 2006, 118 (8): 1853-1861. 10.1002/ijc.21716.CrossRefPubMed
14.
Khan G: Epstein-Barr virus, cytokines, and inflammation: a cocktail for the pathogenesis of Hodgkin's lymphoma?. Exp Hematol. 2006, 34 (4): 399-406. 10.1016/j.exphem.2005.11.008.CrossRefPubMed
15.
Deeb KK, Trump DL, Johnson CS: Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nature reviews. 2007, 7 (9): 684-700. 10.1038/nrc2196.PubMed
16.
Dusso AS, Brown AJ, Slatopolsky E: Vitamin D. Am J Physiol Renal Physiol. 2005, 289 (1): F8-F28. 10.1152/ajprenal.00336.2004.CrossRefPubMed
17.
Hansen CM, Frandsen TL, Brunner N, Binderup L: 1 alpha,25-Dihydroxyvitamin D3 inhibits the invasive potential of human breast cancer cells in vitro. Clin Exp Metastasis. 1994, 12 (3): 195-202. 10.1007/BF01753887.CrossRefPubMed
18.
Mantell DJ, Owens PE, Bundred NJ, Mawer EB, Canfield AE: 1 alpha,25-dihydroxyvitamin D(3) inhibits angiogenesis in vitro and in vivo. Circ Res. 2000, 87 (3): 214-220. 10.1161/01.RES.87.3.214.CrossRefPubMed
19.
Peleg S, Nguyen CV: The importance of nuclear import in protection of the vitamin D receptor from polyubiquitination and proteasome-mediated degradation. J Cell Biochem. 2010, 110 (4): 926-934. 10.1002/jcb.22606.CrossRefPubMed
20.
Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, et al: The nuclear receptor superfamily: the second decade. Cell. 1995, 83 (6): 835-839. 10.1016/0092-8674(95)90199-X.CrossRefPubMed
21.
Yu XP, Hustmyer FG, Garvey WT, Manolagas SC: Demonstration of a 1,25-dihydroxyvitamin D3-responsive protein in human lymphocytes: immunologic crossreactivity and inverse regulation with the vitamin D receptor. Proc Natl Acad Sci U S A. 1991, 88 (19): 8347-8351. 10.1073/pnas.88.19.8347.CrossRefPubMedPubMedCentral
22.
Strom M, Sandgren ME, Brown TA, DeLuca HF: 1,25-Dihydroxyvitamin D3 up-regulates the 1,25-dihydroxyvitamin D3 receptor in vivo. Proc Natl Acad Sci U S A. 1989, 86 (24): 9770-9773. 10.1073/pnas.86.24.9770.CrossRefPubMedPubMedCentral
23.
Lee Y, Inaba M, DeLuca HF, Mellon WS: Immunological identification of 1,25-dihydroxyvitamin D3 receptors in human promyelocytic leukemic cells (HL-60) during homologous regulation. J Biol Chem. 1989, 264 (23): 13701-13705.PubMed
24.
Tetlow LC, Smith SJ, Mawer EB, Woolley DE: Vitamin D receptors in the rheumatoid lesion: expression by chondrocytes, macrophages, and synoviocytes. Ann Rheum Dis. 1999, 58 (2): 118-121. 10.1136/ard.58.2.118.CrossRefPubMedPubMedCentral
25.
Veldman CM, Cantorna MT, DeLuca HF: Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys. 2000, 374 (2): 334-338. 10.1006/abbi.1999.1605.CrossRefPubMed
26.
Kizaki M, Norman AW, Bishop JE, Lin CW, Karmakar A, Koeffler HP: 1,25-Dihydroxyvitamin D3 receptor RNA: expression in hematopoietic cells. Blood. 1991, 77 (6): 1238-1247.PubMed
27.
Mathieu C, Adorini L: The coming of age of 1,25-dihydroxyvitamin D(3) analogs as immunomodulatory agents. Trends Mol Med. 2002, 8 (4): 174-179. 10.1016/S1471-4914(02)02294-3.CrossRefPubMed
28.
Penna G, Adorini L: 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol. 2000, 164 (5): 2405-2411.CrossRefPubMed
29.
Hickish T, Cunningham D, Colston K, Millar BC, Sandle J, Mackay AG, Soukop M, Sloane J: The effect of 1,25-dihydroxyvitamin D3 on lymphoma cell lines and expression of vitamin D receptor in lymphoma. Br J Cancer. 1993, 68 (4): 668-672. 10.1038/bjc.1993.406.CrossRefPubMedPubMedCentral
30.
Lopes N, Sousa B, Martins D, Gomes M, Vieira D, Veronese LA, Milanezi F, Paredes J, Costa JL, Schmitt F: Alterations in Vitamin D signalling and metabolic pathways in breast cancer progression: a study of VDR, CYP27B1 and CYP24A1 expression in benign and malignant breast lesions Vitamin D pathways unbalanced in breast lesions. BMC Cancer. 2010, 10: 483-10.1186/1471-2407-10-483.CrossRefPubMedPubMedCentral
31.
Al-Shami A, Gilbert C, Barabe F, Gaudry M, Naccache PH: Preservation of the pattern of tyrosine phosphorylation in human neutrophil lysates. J Immunol Methods. 1997, 202 (2)): 183-191.CrossRefPubMed
32.
Jeffery LE, Burke F, Mura M, Zheng Y, Qureshi OS, Hewison M, Walker LS, Lammas DA, Raza K, Sansom DM: 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol. 2009, 183 (9): 5458-5467. 10.4049/jimmunol.0803217.CrossRefPubMedPubMedCentral
33.
Bhalla AK, Amento EP, Clemens TL, Holick MF, Krane SM: Specific high-affinity receptors for 1,25-dihydroxyvitamin D3 in human peripheral blood mononuclear cells: presence in monocytes and induction in T lymphocytes following activation. J Clin Endocrinol Metab. 1983, 57 (6): 1308-1310. 10.1210/jcem-57-6-1308.CrossRefPubMed
34.
Morgan JW, Morgan DM, Lasky SR, Ford D, Kouttab N, Maizel AL: Requirements for induction of vitamin D-mediated gene regulation in normal human B lymphocytes. J Immunol. 1996, 157 (7): 2900-2908.PubMed
35.
Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC: 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science (New York, NY. 1983, 221 (4616)): 1181-1183.CrossRef
36.
Morgan JW, Kouttab N, Ford D, Maizel AL: Vitamin D-mediated gene regulation in phenotypically defined human B cell subpopulations. Endocrinology. 2000, 141 (9): 3225-3234. 10.1210/en.141.9.3225.PubMed
37.
Morgan JW, Sliney DJ, Morgan DM, Maizel AL: Differential regulation of gene transcription in subpopulations of human B lymphocytes by vitamin D3. Endocrinology. 1999, 140 (1): 381-391. 10.1210/en.140.1.381.PubMed
38.
Nordstrom M, Hardell L, Magnusson A, Hagberg H, Rask-Andersen A: Occupation and occupational exposure to UV light as risk factors for hairy cell leukaemia evaluated in a case-control study. Eur J Cancer Prev. 1997, 6 (5): 467-472. 10.1097/00008469-199710000-00006.CrossRefPubMed
39.
Bentham G: Association between incidence of non-Hodgkin's lymphoma and solar ultraviolet radiation in England and Wales. BMJ. 1996, 312 (7039): 1128-1131. 10.1136/bmj.312.7039.1128.CrossRefPubMedPubMedCentral
40.
Weihkopf T, Becker N, Nieters A, Mester B, Deeg E, Elsner G, Blettner M, Seidler A: Sun exposure and malignant lymphoma: a population-based case-control study in Germany. Int J Cancer. 2007, 120 (11): 2445-2451. 10.1002/ijc.22492.CrossRefPubMed
41.
Grandin L, Orsi L, Troussard X, Monnereau A, Berthou C, Fenaux P, Marit G, Soubeyran P, Huguet F, Milpied N, et al: UV radiation exposure, skin type and lymphoid malignancies: results of a French case-control study. Cancer Causes Control. 2008, 19 (3): 305-315. 10.1007/s10552-007-9093-6.CrossRefPubMed
42.
Brune V, Tiacci E, Pfeil I, Döring C, Eckerle S, van Noesel CJM, Klapper W, Falini B, Von Heyderbeck AMetzler D, et al: Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analys. J Exp Med. 2008, 205 (10)): 2251-2268.CrossRefPubMedPubMedCentral
43.
Ismail A, Nguyen CV, Ahene A, Fleet JC, Uskokovic MR, Peleg S: Effect of cellular environment on the selective activation of the vitamin D receptor by 1alpha,25-dihydroxyvitamin D3 and its analog 1alpha-fluoro-16-ene-20-epi-23-ene-26,27-bishomo-25-hydroxyvitamin D3 (Ro-26-9228). Mol Endocrinol. 2004, 18 (4): 874-887. 10.1210/me.2003-0310.CrossRefPubMed
44.
Smedby KE, Eloranta S, Duvefelt K, Melbye M, Humphreys K, Hjalgrim H, Chang ET: Vitamin D Receptor Genotypes, Ultraviolet Radiation Exposure, and Risk of Non-Hodgkin Lymphoma. Am J Epidemiol. 2011, 173 (1): 48-54. 10.1093/aje/kwq340.CrossRefPubMed
45.
Pryke AM, Duggan C, White CP, Posen S, Mason RS: Tumor necrosis factor-alpha induces vitamin D-1-hydroxylase activity in normal human alveolar macrophages. J Cell Physiol. 1990, 142 (3): 652-656. 10.1002/jcp.1041420327.CrossRefPubMed
46.
47.
Yenamandra SP, Hellman U, Kempkes B, Darekar SD, Petermann S, Sculley T, Klein G, Kashuba E: Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes. Cell Mol Life Sci. 2010, 67 (24)): 4249-4256.CrossRefPubMed
48.
Whitfield GK, Remus LS, Jurutka PW, Zitzer H, Oza AK, Dang HT, Haussler CA, Galligan MA, Thatcher ML: Encinas Dominguez C et al: Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene. Mol Cell Endocrinol. 2001, 177 (1-2): 145-159. 10.1016/S0303-7207(01)00406-3.CrossRefPubMed
49.
Fang Y, Van Meurs JB, D'Alesio A, Jhamai M, Zhao H, Rivadeneira F, Hofman A, van Leeuwen JP, Jehan F, Pols HA, et al: Promoter and 3'-untranslated-region haplotypes in the vitamin d receptor gene predispose to osteoporotic fracture: the rotterdam study. Am J Hum Genet. 2005, 77 (5)): 807-823.CrossRefPubMedPubMedCentral
50.
Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP: Genetics and biology of vitamin D receptor polymorphisms. Gene. 2004, 338 (2): 143-156. 10.1016/j.gene.2004.05.014.CrossRefPubMed
51.
Purdue MP, Lan Q, Kricker A, Vajdic CM, Rothman N, Armstrong BK: Vitamin D receptor gene polymorphisms and risk of non-Hodgkin's lymphoma. Haematologica. 2007, 92 (8): 1145-1146. 10.3324/haematol.11053.CrossRefPubMed
52.
Purdue MP, Hartge P, Davis S, Cerhan JR, Colt JS, Cozen W, Severson RK, Li Y, Chanock SJ, Rothman N, et al: Sun exposure, vitamin D receptor gene polymorphisms and risk of non-Hodgkin lymphoma. Cancer Causes Control. 2007, 18 (9): 989-999. 10.1007/s10552-007-9039-z.CrossRefPubMed
Metadata
Title
Vitamin D3receptor is highly expressed in Hodgkin’s lymphoma
Authors
Christoph Renné
Alexander H Benz
Martin L Hansmann
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2012
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-12-215

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