Ovarian Cancer: Interplay of Vitamin D Signaling and miRNA Action

  • Attar, Rukset (Department of Obstetrics and Gynecology, Yeditepe University Hospital) ;
  • Gasparri, Maria Luisa (Department of Gynecology and Obstetrics, Sapienza University of Rome) ;
  • Di Donato, Violante (Department of Gynecology and Obstetrics, Sapienza University of Rome) ;
  • Yaylim, Ilhan (Department of Molecular Medicine, Institute of Experimental Medicine, Istanbul University) ;
  • Halim, Talha Abdul (Department of Obstetrics and Gynecology) ;
  • Zaman, Farrukh (Department of Obstetrics and Gynecology) ;
  • Farooqi, Ammad Ahmad (Laboratory for Translational Oncology and Personalized Medicine)
  • Published : 2014.04.30


Increasing attention is being devoted to the mechanisms by which cells receive signals and then translate these into decisions for growth, death, or migration. Recent findings have presented significant breakthroughs in developing a deeper understanding of the activation or repression of target genes and proteins in response to various stimuli and of how they are assembled during signal transduction in cancer cells. Detailed mechanistic insights have unveiled new maps of linear and integrated signal transduction cascades, but the multifaceted nature of the pathways remains unclear. Although new layers of information are being added regarding mechanisms underlying ovarian cancer and how polymorphisms in VDR gene influence its development, the findings of this research must be sequentially collected and re-interpreted. We divide this multi-component review into different segments: how vitamin D modulates molecular network in ovarian cancer cells, how ovarian cancer is controlled by tumor suppressors and oncogenic miRNAs and finally how vitamin D signaling regulates miRNA expression. Intra/inter-population variability is insufficiently studied and a better understanding of genetics of population will be helpful in getting a step closer to personalized medicine.


  1. Xu Y, He B, Pan Y, et al (2014). Systematic review and metaanalysis on vitamin D receptor polymorphisms and cancer risk. Tumour Biol, 35, 4153-69
  2. Wan HF, Yu LH, Wu JL, et al (2013). Effect of diallyl trisulfide on human ovarian cancer SKOV- 3/DDP cell apoptosis. Asian Pac J Cancer Prev, 14, 7197-201.
  3. Wang Z, Ting Z, Li Y, et al (2013). microRNA-199a is able to reverse cisplatin resistance in human ovarian cancer cells through the inhibition of mammalian target of rapamycin. Oncol Lett, 6, 789-794.
  4. Wu Y, Zhang X, Lin L, et al (2014). Aberrant methylation of RASSF2A in tumors and plasma of patients with epithelial ovarian cancer. Asian Pac J Cancer Prev, 15, 1171-6.
  5. Yin L, Grandi N, Raum E, (2011). Meta-analysis: circulating vitamin D and ovarian cancer risk. Gynecol Oncol, 121, 69-75.
  6. Zhang Y, Tong SC, Guan LH, (2013). Meta-analysis of the relation between vitamin D receptor gene BsmI polymorphism and susceptibility to ovarian cancer. Tumour Biol, 34, 3317-21.
  7. Padi SK, Zhang Q, Rustum YM, Morrison C, Guo B (2013). MicroRNA-627 mediates the epigenetic mechanisms of vitamin D to suppress proliferation of human colorectal cancer cells and growth of xenograft tumors in mice. Gastroenterology, 145, 437-46.
  8. Li H, Cai Q, Godwin AK, Zhang R (2010). Enhancer of zeste homolog 2 promotes the proliferation and invasion of epithelial ovarian cancer cells. Mol Cancer Res, 8, 1610-8.
  9. Min D, Lv XB, Wang X, et al (2013). Downregulation of miR-302c and miR-520c by 1,25(OH)2D3 treatment enhances the susceptibility of tumour cells to natural killer cell-mediated cytotoxicity. Br J Cancer, 109, 723-30.
  10. Moore RG, Lange TS, Robinson K, et al (2012). Efficacy of a non-hypercalcemic vitamin-D2 derived anti-cancer agent (MT19c) and inhibition of fatty acid synthesis in an ovarian cancer xenograft model. PLoS One, 7, e34443.
  11. Patel JB, Patel KD, Patel SR, et al (2012). Recent candidate molecular markers: vitamin D signaling and apoptosis specific regulator of p53 (ASPP) in breast cancer. Asian Pac J Cancer Prev, 13, 1727-35.
  12. Qin X, Lu Y, Qin A, et al (2013). Vitamin D receptor BsmІ polymorphism and ovarian cancer risk: a meta-analysis. Int J Gynecol Cancer, 23, 1178-83.
  13. Shen Z, Zhang X, Tang J, et al (2011). The coupling of epidermal growth factor receptor down regulation by 1alpha,25-dihydroxyvitamin D3 to the hormone-induced cell cycle arrest at the G1-S checkpoint in ovarian cancer cells. Mol Cell Endocrinol, 338, 58-67.
  14. Sun C, Li N, Zhou B, et al (2013). miR-222 is upregulated in epithelial ovarian cancer and promotes cell proliferation by downregulating P27kip1. Oncol Lett, 6, 507-512.
  15. Walentowicz-Sadłecka M, Sadłecki P, Walentowicz P, Grabiec M (2013). The role of vitamin D in the carcinogenesis of breast and ovarian cancer. Ginekol Pol, 84, 305-8.
  16. Huang JW, Wang Y, Dhillon KK, et al (2013). Systematic screen identifies miRNAs that target RAD51 and RAD51D to enhance chemosensitivity. Mol Cancer Res, 11, 1564-73.
  17. Guo Y, Tian P, Yang C, et al (2013). Silencing the doublestranded RNA binding protein DGCR8 inhibits ovarian cancer cell proliferation, migration, and invasion. Pharm Res, Oct 12, [Epub ahead of print].
  18. Hossein G, Keshavarz M, Ahmadi S, Naderi N (2013). Synergistic effects of PectaSol-C modified citrus pectin an inhibitor of galectin-3 and paclitaxel on apoptosis of human SKOV-3 ovarian cancer cells. Asian Pac J Cancer Prev, 14, 7561-8.
  19. House CD, Hernandez L, Annunziata CM (2014). Recent technological advances in using mouse models to study ovarian cancer. Front Oncol, 13, 4-26.
  20. Ji T, Zheng ZG, Wang FM, et al (2014). Differential microRNA expression by solexa sequencing in the sera of ovarian cancer patients. Asian Pac J Cancer Prev, 15, 1739-43.
  21. Kasiappan R, Shen Z, Tse AK, et al (2012). 1,25-Dihydroxyvitamin D3 suppresses telomerase expression and human cancer growth through microRNA-498. J Biol Chem, 287, 41297-309.
  22. Kawar N, Maclaughlan S, Horan TC, et al (2013). PT19c, another nonhypercalcemic vitamin D2 derivative, demonstrates antitumor efficacy in epithelial ovarian and endometrial cancer models. Genes Cancer, 4, 524-34.
  23. Kuang Y, Cai J, Li D, (2013). Repression of dicer is associated with invasive phenotype and chemoresistance in ovarian cancer. Oncol Lett, 5, 1149-54.
  24. Li D, Wang X, Wu JL, et al (2013). Tumor-produced versican V1 enhances hCAP18/LL-37 expression in macrophages through activation of TLR2 and vitamin D3 signaling to promote ovarian cancer progression in vitro. PLoS One, 8, 56616.
  25. Giangreco AA, Vaishnav A, Wagner D, et al (2013) Tumor suppressor microRNAs, miR-100 and-125b, are regulated by 1,25-dihydroxyvitamin D in primary prostate cells and in patient tissue. Cancer Prev Res, 6, 483-94.
  26. Alvarez-Diaz S, Valle N, Ferrer-Mayorga G, et al (2012) MicroRNA-22 is induced by vitamin D and contributes to its antiproliferative, antimigratory and gene regulatory effects in colon cancer cells. Hum Mol Genet, 21, 2157-65.
  27. Brard L, Lange TS, Robison K, et al (2011). Evaluation of the first ergocalciferol-derived, non hypercalcemic anti-cancer agent MT19c in ovarian cancer SKOV-3 cell lines. Gynecol Oncol, 123, 370-8.
  28. Cai J, Yang C, Yang Q, (2013). Deregulation of let-7e in epithelial ovarian cancer promotes the development of resistance to cisplatin. Oncogenesis, 7, 2-75.
  29. Gocek E, Wang X, Liu X, Liu CG, Studzinski GP (2011). MicroRNA-32 upregulation by 1,25-dihydroxyvitamin D3 in human myeloid leukemia cells leads to bim targeting and inhibition of AraC-induced apoptosis. Cancer Res, 71, 6230-9.
  30. Guan H, Liu C, Chen Z, et al (2013). 1,25-Dihydroxyvitamin D3 up-regulates expression of hsa-let-7a-2 through the interaction of VDR/VDRE in human lung cancer A549 cells. Gene, 522, 142-6.

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