Correlation between Expression of RARa Transcription Factor and Genes of VEGFR3-Dependent Signaling System in Multiple Myeloma

EXPERIMENTAL STUDIES , ,

NN Kalitin, IV Buravtsova

N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Nikolai Nikolaevich Kalitin, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-17-69; e-mail: f.oskolov@mail.ru

For citation: Kalitin NN, Buravtsova IV. Correlation between Expression of RARa Transcription Factor and Genes of VEGFR3-Dependent Signaling System in Multiple Myeloma. Clinical oncohematology. 2015;8(1):31–5 (In Russ).

ABSTRACT

Background. All-trans retinoic acid (ATRA) is a natural metabolite of vitamin A, which can regulate the gene expression by means of interaction between different types of nuclear retinoic acid receptors (RARs). It has been demonstrated that it may lead to suppression of in vivo and in vitro tumor cell growth and can contribute to its survival. For example, in a number of studies, it has been demonstrated that one of RAR subtypes, RARa, modulates expression of a number of vascular endothelial growth factors (VEGFs), mainly VEGF-A. At the same time, the exact mechanisms regulating the RARa-mediated regulation of VEGF (especially VEGF-C and VEGF-D and their receptor VEGFR3) expression are still unclear.

Methods. Changes in expression of mRNAs of VEGF-C, VEGF-D genes and their receptor VEGFR3 in a group of 17 multiple myeloma patients before and after treatment were analyzed in the article. The obtained data were then compared with changes in gene expression of the RARa receptor.

Results. It has been found that overall levels of VEGF-C, VEGF-D and VEGFR3 gene expression were reduced in response to the therapy. Changes in expression of these genes correlated with the RARa expression.

Conclusions. The correlation between VEGF-C, VEGF-D and VEGFR3 expression and RARa expression could indicate a possible involvement of RARa- protein in regulation of VEGFR3-associated signaling system gene expression.

Scientific value. These results may describe a possible mechanism of VEGF-C, VEGF-D and VEGFR3 expression by the RARa transcription factor.

Keywords: multiple myeloma, gene expression, VEGFR3-dependent system, RARa.

Received: August 27, 2014

Accepted: October 20, 2014

Read in  PDF (RUS)pdficon

REFERENCES

  1. Neufeld G. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 1999;13(1):9–22.
  2. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003;9(6):677–84. doi: 10.1038/nm0603-677.
  3. Ristimaki A, Narko K, Enholm B, et al. Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-C. J Biol Chem. 1998;273(14):8413–8.
  4. Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J. 1996;10(9):940–54.
  5. Leid M, Kastner P, Chambon P. Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci. 1992;17(10):427–33. doi: 10.1016/0968-0004(92)90014-z.
  6. Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell. 1995;83(6):841–50. doi: 10.1016/0092-8674(95)90200-7.
  7. Delacroix L, Moutier E, Altobelli G, et al. Cell-specific interaction of retinoic acid receptors with target genes in mouse embryonic fibroblasts and embryonic stem cells. Mol Cell Biol. 2010;30(1):231–44. doi: 10.1128/mcb.00756-09.
  8. Eifert C, Sangster-Guity N, Yu LM, et al. Global gene expression profiles associated with retinoic acid-induced differentiation of embryonal carcinoma cells. Mol Reprod Dev. 2006;73(7):796–824. doi: 10.1002/mrd.20444.
  9. Maeno T, Tanaka T, Sando Y, et al. Stimulation of vascular endothelial growth factor gene transcription by all trans retinoic acid through Sp1 and Sp3 sites in human bronchioloalveolar carcinoma cells. Am J Respir Cell Mol Biol. 2002;26(2):246–53. doi: 10.1165/ajrcmb.26.2.4509.
  10. Tsuzuki S, Kitajima K, Nakano T, et al. Cross talk between retinoic acid signaling and transcription factor GATA-2. Mol Cell Biol. 2004;24(15):6824–36. doi: 10.1128/mcb.24.15.6824-6836.2004.
  11. Kappel A, Schlaeger TM, Flamme I, et al. Role of SCL/Tal-1, GATA, and its transcription factor binding sites for the regulation of flk-1 expression during murine vascular development. Blood. 2000;96(9):3078–85.
  12. Durie BGM, Salmon SE. A clinical staging system for multiple myeloma. Cancer. 1975;36(3):842–54. doi: 10.1002/1097-0142(197509)36:3<842::aid-cncr2820360303>3.0.co;2-u.
  13. Rajkumar SV, Leong T, Roche PC, et al. Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin Cancer Res. 2000;6(8):3111–6.
  14. Vacca A, Ribatti D, Presta M, et al. Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood. 1999;93(9):3064–73.
  15. Schafer G, Wissmann C, Hertel J, et al. Regulation of vascular endothelial growth factor D by orphan receptors hepatocyte nuclear factor-4A and chicken ovalbumin upstream promoter transcription factors 1 and 2. Cancer Res. 2008;68(2):457–66. doi: 10.1158/0008-5472.CAN-07-5136.
  16. Калитин Н.Н., Какпакова Е.С., Карамышева А.Ф. Влияние ретиноевой кислоты на экспрессию мРНК генов факторов роста эндотелия сосудов VEGF и рецептора VEGFR1 в культурах клеток множественной миеломы человека. Вопросы биологической, медицинской и фармацевтической химии. 2012;10:64–8.
    [Kalitin NN, Kakpakova ES, Karamysheva AF. Effect of retinoid acid on expression of mRNA in genes of vascular endothelial growth factor VEGF and VEGFR1 receptor in cultures of human multiple myeloma cells. Voprosy biologicheskoi, meditsinskoi i farmatsevticheskoi khimii. 2012;10:64–8. (In Russ)]