1α,25‑Dihydroxyvitamin D3 restrains stem cell‑like properties of ovarian cancer cells by enhancing vitamin D receptor and suppressing CD44

Ji,Mintao; Liu,Lizhi; Hou,Yongfeng; Li,Bingyan

doi:10.3892/or.2019.7116

1α,25‑Dihydroxyvitamin D3 restrains stem cell‑like properties of ovarian cancer cells by enhancing vitamin D receptor and suppressing CD44

Authors:
- Mintao Ji
- Lizhi Liu
- Yongfeng Hou
- Bingyan Li
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Affiliations: Department of Nutrition and Food Hygiene, Soochow University of Public Health, Suzhou, Jiangsu 215123, P.R. China, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‑Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, P.R. China
Published online on: April 15, 2019 https://doi.org/10.3892/or.2019.7116
Pages: 3393-3403

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Abstract

Scientific evidence linking vitamin D with various cancer types is growing, but the effects of vitamin D on ovarian cancer stem cell‑like cells (CSCs) are largely unknown. The present study aimed to examine whether vitamin D was able to restrain the stemness of ovarian cancer. A side population (SP) from malignant ovarian surface epithelial cells was identified as CSCs, in vitro and in vivo. Furthermore, 1α,25‑dihydroxyvitamin D3 [1α,25(OH)2D3] treatment inhibited the self‑renewal capacity of SP cells by decreasing the sphere formation rate and by suppressing the mRNA expression levels of cluster of differentiation CD44, NANOG, OCT4, SOX2, Krüppel‑like factor 4 and adenosine triphosphate binding cassette subfamily G member 2. Additionally, 1α,25(OH)2D3 treatment decreased the expression of Cyclin D1, whereas it increased the expression of β‑catenin and vitamin D receptor (VDR). Notably, immunofluorescence staining verified that 1α,25(OH)2D3 promoted the expression of β‑catenin in the cytoplasm. Furthermore, vitamin D3 delayed the onset of tumor formation derived from injection of ovarian CSCs to nude mice, by reducing CD44 and enhancing β‑catenin expressions in vivo. In conclusion, 1α,25(OH)2D3 restrains the stem cell‑like properties of ovarian cancer cells by enhancing the expression of VDR, by promoting the expression of β‑catenin in the cytoplasm, and by suppressing the expression of CD44. These findings provide a novel insight into the functions of vitamin D in diminishing the stemness of cancer CSCs.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
2	Bast RC Jr, Hennessy B and Mills GB: The biology of ovarian cancer: New opportunities for translation. Nat Rev Cancer. 9:415–428. 2009. View Article : Google Scholar : PubMed/NCBI
3	Kurman RJ and Shih Ie M: The origin and pathogenesis of epithelial ovarian cancer: A proposed unifying theory. Am J Surg Pathol. 34:433–443. 2010. View Article : Google Scholar : PubMed/NCBI
4	Chang HL, MacLaughlin DT and Donahoe PK: Somatic stem cells of the ovary and their relationship to human ovarian cancers. StemBook; Cambridge MA: Harvard Stem Cell Institute: 2008–2009
5	Szotek PP, Chang HL, Brennand K, Fujino A, Pieretti-Vanmarcke R, Lo Celso C, Dombkowski D, Preffer F, Cohen KS, Teixeira J, et al: Normal ovarian surface epithelial label-retaining cells exhibit stem/progenitor cell characteristics. Proc Natl Acad Sci USA. 105:12469–12473. 2008. View Article : Google Scholar : PubMed/NCBI
6	Flesken-Nikitin A, Hwang CI, Cheng CY, Michurina TV, Enikolopov G and Nikitin AY: Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche. Nature. 495:241–245. 2013. View Article : Google Scholar : PubMed/NCBI
7	Aguilar-Gallardo C, Rutledge EC, Martínez-Arroyo AM, Hidalgo JJ, Domingo S and Simón C: Overcoming challenges of ovarian cancer stem cells: Novel therapeutic approaches. Stem Cell Rev. 8:994–1010. 2012. View Article : Google Scholar : PubMed/NCBI
8	Zhao J: Cancer stem cells and chemoresistance: The smartest survives the raid. Pharmacol Ther. 160:145–158. 2016. View Article : Google Scholar : PubMed/NCBI
9	Zhang S, Cui B, Lai H, Liu G, Ghia EM, Widhopf GF II, Zhang Z, Wu CC, Chen L, Wu R, et al: Ovarian cancer stem cells express ROR1, which can be targeted for anti-cancer-stem-cell therapy. Proc Natl Acad Sci USA. 111:17266–17271. 2014. View Article : Google Scholar : PubMed/NCBI
10	Wang Y, Cardenas H, Fang F, Condello S, Taverna P, Segar M, Liu Y, Nephew KP and Matei D: Epigenetic targeting of ovarian cancer stem cells. Cancer Res. 74:4922–4936. 2014. View Article : Google Scholar : PubMed/NCBI
11	Chau WK, Ip CK, Mak AS, Lai HC and Wong AS: c-Kit mediates chemoresistance and tumor-initiating capacity of ovarian cancer cells through activation of Wnt/β-catenin-ATP-binding cassette G2 signaling. Oncogene. 32:2767–2781. 2013. View Article : Google Scholar : PubMed/NCBI
12	Abubaker K, Latifi A, Luwor R, Nazaretian S, Zhu H, Quinn MA, Thompson EW, Findlay JK and Ahmed N: Short-term single treatment of chemotherapy results in the enrichment of ovarian cancer stem cell-like cells leading to an increased tumor burden. Mol Cancer. 12:242013. View Article : Google Scholar : PubMed/NCBI
13	Feldman D, Krishnan AV, Swami S, Giovannucci E and Feldman BJ: The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer. 14:342–357. 2014. View Article : Google Scholar : PubMed/NCBI
14	Pervin S, Hewison M, Braga M, Tran L, Chun R, Karam A, Chaudhuri G, Norris K and Singh R: Down-regulation of vitamin D receptor in mammospheres: Implications for vitamin D resistance in breast cancer and potential for combination therapy. PLoS One. 8:e532872013. View Article : Google Scholar : PubMed/NCBI
15	Pereira F, Larriba MJ and Muñoz A: Vitamin D and colon cancer. Endocr Relat Cancer. 19:R51–R71. 2012. View Article : Google Scholar : PubMed/NCBI
16	Larriba MJ and Muñoz A: SNAIL vs. vitamin D receptor expression in colon cancer: Therapeutics implications. Br J Cancer. 92:985–989. 2005. View Article : Google Scholar : PubMed/NCBI
17	Hou YF, Gao SH, Wang P, Zhang HM, Liu LZ, Ye MX, Zhou GM, Zhang ZL and Li BY: 1α,25(OH)₂D₃ suppresses the migration of ovarian cancer SKOV-3 cells through the inhibition of epithelial-mesenchymal transition. Int J Mol Sci. 17:12852016. View Article : Google Scholar :
18	Maund SL, Barclay WW, Hover LD, Axanova LS, Sui G, Hipp JD, Fleet JC, Thorburn A and Cramer SD: Interleukin-1α mediates the antiproliferative effects of 1,25-dihydroxyvitamin D₃ in prostate progenitor/stem cells. Cancer Res. 71:5276–5286. 2011. View Article : Google Scholar : PubMed/NCBI
19	Choudhury S, Almendro V, Merino VF, Wu Z, Maruyama R, Su Y, Martins FC, Fackler MJ, Bessarabova M, Kowalczyk A, et al: Molecular profiling of human mammary gland links breast cancer risk to a p27⁺ cell population with progenitor characteristics. Cell Stem Cell. 13:117–130. 2013. View Article : Google Scholar : PubMed/NCBI
20	So JY, Lee HJ, Smolarek AK, Paul S, Wang CX, Maehr H, Uskokovic M, Zheng X, Conney AH, Cai L, et al: A novel Gemini vitamin D analog represses the expression of a stem cell marker CD44 in breast cancer. Mol Pharmacol. 79:360–367. 2011. View Article : Google Scholar : PubMed/NCBI
21	So JY, Wahler J, Das Gupta S, Salerno DM, Maehr H, Uskokovic M and Suh N: HES1-mediated inhibition of Notch1 signaling by a Gemini vitamin D analog leads to decreased CD44⁺/CD24^−/low tumor-initiating subpopulation in basal-like breast cancer. J Steroid Biochem Mol Biol. 148:111–121. 2015. View Article : Google Scholar : PubMed/NCBI
22	Yasuda K, Torigoe T, Morita R, Kuroda T, Takahashi A, Matsuzaki J, Kochin V, Asanuma H, Hasegawa T, Saito T, et al: Ovarian cancer stem cells are enriched in side population and aldehyde dehydrogenase bright overlapping population. PLoS One. 8:e681872013. View Article : Google Scholar : PubMed/NCBI
23	Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, Dinulescu DM, Connolly D, Foster R, Dombkowski D, Preffer F, Maclaughlin DT and Donahoe PK: Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci USA. 103:11154–11159. 2006. View Article : Google Scholar : PubMed/NCBI
24	Hu L, McArthur C and Jaffe RB: Ovarian cancer stem-like side-population cells are tumourigenic and chemoresistant. Br J Cancer. 102:1276–1283. 2010. View Article : Google Scholar : PubMed/NCBI
25	Rizzo S, Hersey JM, Mellor P, Dai W, Santos-Silva A, Liber D, Luk L, Titley I, Carden CP, Box G, et al: Ovarian cancer stem cell-like side populations are enriched following chemotherapy and overexpress EZH2. Mol Cancer Ther. 10:325–335. 2011. View Article : Google Scholar : PubMed/NCBI
26	Sales-Pardo I, Avendaño A, Martinez-Muñoz V, García-Escarp M, Celis R, Whittle P, Barquinero J, Domingo JC, Marin P and Petriz J: Flow cytometry of the side population: Tips & tricks. Cell Oncol. 28:37–53. 2006.PubMed/NCBI
27	Roby KF, Taylor CC, Sweetwood JP, Cheng Y, Pace JL, Tawfik O, Persons DL, Smith PG and Terranova PF: Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogenesis. 21:585–591. 2000. View Article : Google Scholar : PubMed/NCBI
28	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
29	de la Mare JA, Jurgens T and Edkins AL: Extracellular Hsp90 and TGFβ regulate adhesion, migration and anchorage independent growth in a paired colon cancer cell line model. BMC cancer. 17:2022017. View Article : Google Scholar : PubMed/NCBI
30	McCloskey CW, Goldberg RL, Carter LE, Gamwell LF, Al-Hujaily EM, Collins O, Macdonald EA, Garson K, Daneshmand M, Carmona E, et al: A new spontaneously transformed syngeneic model of high-grade serous ovarian cancer with a tumor-initiating cell population. Front Oncol. 4:532014. View Article : Google Scholar : PubMed/NCBI
31	Lobo NA, Shimono Y, Qian D and Clarke MF: The biology of cancer stem cells. Annu Rev Cell Dev Biol. 23:675–699. 2007. View Article : Google Scholar : PubMed/NCBI
32	Gerweck LE and Wakimoto H: At the crossroads of cancer stem cells, radiation biology, and radiation oncology. Cancer Res. 76:994–998. 2016. View Article : Google Scholar : PubMed/NCBI
33	Steg AD, Bevis KS, Katre AA, Ziebarth A, Dobbin ZC, Alvarez RD, Zhang K, Conner M and Landen CN: Stem cell pathways contribute to clinical chemoresistance in ovarian cancer. Clin Cancer Res. 18:869–881. 2012. View Article : Google Scholar : PubMed/NCBI
34	Nuti SV, Mor G, Li P and Yin G: TWIST and ovarian cancer stem cells: Implications for chemoresistance and metastasis. Oncotarget. 5:7260–7271. 2014. View Article : Google Scholar : PubMed/NCBI
35	Huang R, Wu D, Yuan Y, Li X, Holm R, Trope CG, Nesland JM and Suo Z: CD117 expression in fibroblasts-like stromal cells indicates unfavorable clinical outcomes in ovarian carcinoma patients. PLoS One. 9:e1122092014. View Article : Google Scholar : PubMed/NCBI
36	Chen J, Wang J, Chen D, Yang J, Yang C, Zhang Y, Zhang H and Dou J: Evaluation of characteristics of CD44⁺CD117⁺ ovarian cancer stem cells in three dimensional basement membrane extract scaffold versus two dimensional monocultures. BMC Cell Biol. 14:72013. View Article : Google Scholar : PubMed/NCBI
37	Yanamoto S, Kawasaki G, Yamada S, Yoshitomi I, Kawano T, Yonezawa H, Rokutanda S, Naruse T and Umeda M: Isolation and characterization of cancer stem-like side population cells in human oral cancer cells. Oral Oncol. 47:855–860. 2011. View Article : Google Scholar : PubMed/NCBI
38	Ruan Z, Liu J and Kuang Y: Isolation and characterization of side population cells from the human ovarian cancer cell line SK-OV-3. Exp Ther Med. 10:2071–2078. 2015. View Article : Google Scholar : PubMed/NCBI
39	Hendrickson WK, Flavin R, Kasperzyk JL, Fiorentino M, Fang F, Lis R, Fiore C, Penney KL, Ma J, Kantoff PW, et al: Vitamin D receptor protein expression in tumor tissue and prostate cancer progression. J Clin Oncol. 29:2378–2385. 2011. View Article : Google Scholar : PubMed/NCBI
40	Ditsch N, Toth B, Mayr D, Lenhard M, Gallwas J, Weissenbacher T, Dannecker C, Friese K and Jeschke U: The association between vitamin D receptor expression and prolonged overall survival in breast cancer. J Histochem Cytochem. 60:121–129. 2012. View Article : Google Scholar : PubMed/NCBI
41	Jiang F, Li P, Fornace AJ Jr, Nicosia SV and Bai W: G₂/M arrest by 1,25-dihydroxyvitamin D₃ in ovarian cancer cells mediated through the induction of GADD45 via an exonic enhancer. J Biol Chem. 278:48030–48040. 2003. View Article : Google Scholar : PubMed/NCBI
42	Jiang F, Bao J, Li P, Nicosia SV and Bai W: Induction of ovarian cancer cell apoptosis by 1,25-dihydroxyvitamin D₃ through the down-regulation of telomerase. J Biol Chem. 279:53213–53221. 2004. View Article : Google Scholar : PubMed/NCBI
43	Zhang X, Jiang F, Li P, Li C, Ma Q, Nicosia SV and Bai W: Growth suppression of ovarian cancer xenografts in nude mice by vitamin D analogue EB1089. Clin Cancer Res. 11:323–328. 2005.PubMed/NCBI
44	Hiraga T, Ito S and Nakamura H: Cancer stem-like cell marker CD44 promotes bone metastases by enhancing tumorigenicity, cell motility, and hyaluronan production. Cancer Res. 73:4112–4122. 2013. View Article : Google Scholar : PubMed/NCBI
45	Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, Patrawala L, Yan H, Jeter C, Honorio S, et al: The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 17:211–215. 2011. View Article : Google Scholar : PubMed/NCBI
46	Kashyap V, Rezende NC, Scotland KB, Shaffer SM, Persson JL, Gudas LJ and Mongan NP: Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the NANOG, OCT4, and SOX2 pluripotency transcription factors with polycomb repressive complexes and stem cell microRNAs. Stem Cells Dev. 18:1093–1108. 2009. View Article : Google Scholar : PubMed/NCBI
47	Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner RG, et al: Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 122:947–956. 2005. View Article : Google Scholar : PubMed/NCBI
48	Bourguignon LY, Wong G, Earle C and Chen L: Hyaluronan-CD44v3 interaction with Oct4-Sox2-Nanog promotes miR-302 expression leading to self-renewal, clonal formation, and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma. J Biol Chem. 287:32800–32824. 2012. View Article : Google Scholar : PubMed/NCBI
49	Schneider S, Steinbeisser H, Warga RM and Hausen P: Beta-catenin translocation into nuclei demarcates the dorsalizing centers in frog and fish embryos. Mech Dev. 57:191–198. 1996. View Article : Google Scholar : PubMed/NCBI
50	Hoffmeyer K, Raggioli A, Rudloff S, Anton R, Hierholzer A, Del Valle I, Hein K, Vogt R and Kemler R: Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 336:1549–1554. 2012. View Article : Google Scholar : PubMed/NCBI
51	Lee E, Madar A, David G, Garabedian MJ, Dasgupta R and Logan SK: Inhibition of androgen receptor and beta-catenin activity in prostate cancer. Proc Natl Acad Sci USA. 110:15710–15715. 2013. View Article : Google Scholar : PubMed/NCBI
52	Li S, Li S, Sun Y and Li L: The expression of beta-catenin in different subtypes of breast cancer and its clinical significance. Tumour Biol. 35:7693–7698. 2014. View Article : Google Scholar : PubMed/NCBI
53	Wang H, Wang H, Makki MS, Wen J, Dai Y, Shi Q, Liu Q, Zhou X and Wang J: Overexpression of β-catenin and cyclinD1 predicts a poor prognosis in ovarian serous carcinomas. Int J Clin Exp Pathol. 7:264–271. 2014.PubMed/NCBI
54	Clevers H and Nusse R: Wnt/β-catenin signaling and disease. Cell. 149:1192–1205. 2012. View Article : Google Scholar : PubMed/NCBI
55	Sebio A, Kahn M and Lenz HJ: The potential of targeting Wnt/β-catenin in colon cancer. Expert Opin Ther Targets. 18:611–615. 2014. View Article : Google Scholar : PubMed/NCBI
56	Larriba MJ, Ordóñez-Moran P, Chicote I, Martín-Fernández G, Puig I, Muñoz A and Pálmer HG: Vitamin D receptor deficiency enhances Wnt/beta-catenin signaling and tumor burden in colon cancer. PLoS One. 6:e235242011. View Article : Google Scholar : PubMed/NCBI
57	Jiang YJ, Teichert AE, Fong F, Oda Y and Bikle DD: 1α,25(OH)2-dihydroxyvitamin D₃/VDR protects the skin from UVB-induced tumor formation by interacting with the beta-catenin pathway. J Steroid Biochem Mol Biol. 136:229–232. 2013. View Article : Google Scholar : PubMed/NCBI
58	Pálmer HG, González-Sancho JM, Espada J, Berciano MT, Puig I, Baulida J, Quintanilla M, Cano A, de Herreros AG, Lafarga M and Muñoz A: Vitamin D₃ promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol. 154:369–387. 2001. View Article : Google Scholar : PubMed/NCBI