CD24 expression is a marker for predicting clinical outcome and regulates the epithelial-mesenchymal transition in ovarian cancer via both the Akt and ERK pathways

Nakamura,Kiyoko; Terai,Yoshito; Tanabe,Akiko; Ono,Yoshihiro   J.; Hayashi,Masami; Maeda,Kazuya; Fujiwara,Satoe; Ashihara,Keisuke; Nakamura,Michihiko; Tanaka,Yoshimichi; Tanaka,Tomohito; Tsunetoh,Satoshi; Sasaki,Hiroshi; Ohmichi,Masahide

doi:10.3892/or.2017.5583

CD24 expression is a marker for predicting clinical outcome and regulates the epithelial-mesenchymal transition in ovarian cancer via both the Akt and ERK pathways

Authors:
- Kiyoko Nakamura
- Yoshito Terai
- Akiko Tanabe
- Yoshihiro J. Ono
- Masami Hayashi
- Kazuya Maeda
- Satoe Fujiwara
- Keisuke Ashihara
- Michihiko Nakamura
- Yoshimichi Tanaka
- Tomohito Tanaka
- Satoshi Tsunetoh
- Hiroshi Sasaki
- Masahide Ohmichi
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki-city, Osaka 569-8686, Japan
Published online on: April 19, 2017 https://doi.org/10.3892/or.2017.5583
Pages: 3189-3200
Copyright: © Nakamura et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The degree of peritoneal dissemination and chemotherapy-resistant tumors is related to the prognosis in patients with advanced-stage ovarian cancer. The epithelial-mesenchymal-transition (EMT) is a multifaceted pathological program that endows cancer cells with the ability to invade and disseminate. CD24 is frequently overexpressed in various human cancers and is correlated with a poor prognosis. We herein examined the functions of CD24 in human ovarian cancer cell lines and evaluated how it contributes to the molecular mechanism underlying the regeneration of cancer stem-like cells (CSCs) through the EMT mechanism in ovarian carcinoma. We demonstrated that CD24 was expressed in 70.1% of primary ovarian carcinoma tissues, which were obtained from 174 patients, and that the expression of CD24 was an independent predictor of survival in patients with ovarian cancer. The expression of CD24 has been found to be correlated with the FIGO stage, presence of peritoneal and lymph node metastasis. CD24 induces the EMT phenomenon, which is involved in cell invasion, the highly proliferative phenotype, colony formation and which is associated with cisplatin resistance and the properties of CSCs, via the activation of PI3K/Akt, NF-κB and ERK in Caov-3 cisplatin-resistant cell lines. CD24-positive ovarian carcinomas have been shown to have a greater potential for intra-abdominal tumor cell dissemination in in vivo models. Our findings suggest that CD24 induced the EMT phenomenon in ovarian cancer, and that CD24 amplified cell growth-related intracellular signaling via the PI3K/Akt and MAPK pathways by affecting the EMT signal pathways. We believe that CD24 is a key molecule of metastatic progression in the EMT phenomenon and a promising therapeutic target for advanced ovarian cancer.

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1	Ozols RF: Treatment goals in ovarian cancer. Int J Gynecol Cancer. 15:3–11. 2005. View Article : Google Scholar : PubMed/NCBI
2	Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009. View Article : Google Scholar : PubMed/NCBI
3	Kang Y and Massagué J: Epithelial-mesenchymal transitions: Twist in development and metastasis. Cell. 118:277–279. 2004. View Article : Google Scholar : PubMed/NCBI
4	Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2:442–454. 2002. View Article : Google Scholar : PubMed/NCBI
5	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
6	Zeisberg M and Neilson EG: Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 119:1429–1437. 2009. View Article : Google Scholar : PubMed/NCBI
7	Krantz SB, Shields MA, Dangi-Garimella S, Munshi HG and Bentrem DJ: Contribution of epithelial-to-mesenchymal transition and cancer stem cells to pancreatic cancer progression. J Surg Res. 173:105–112. 2012. View Article : Google Scholar : PubMed/NCBI
8	Dalerba P, Cho RW and Clarke MF: Cancer stem cells: Models and concepts. Annu Rev Med. 58:267–284. 2007. View Article : Google Scholar : PubMed/NCBI
9	Kay R, Rosten PM and Humphries RK: CD24, a signal transducer modulating B cell activation responses, is a very short peptide with a glycosyl phosphatidylinositol membrane anchor. J Immunol. 147:1412–1416. 1991.PubMed/NCBI
10	Aigner S, Ruppert M, Hubbe M, Sammar M, Sthoeger Z, Butcher EC, Vestweber D, Altevogt P and Kaufmann SHE: Heat stable antigen (mouse CD24) supports myeloid cell binding to endothelial and platelet P-selectin. Int Immunol. 7:1557–1565. 1995. View Article : Google Scholar : PubMed/NCBI
11	Lee KM, Ju JH, Jang K, Yang W, Yi JY, Noh DY and Shin I: CD24 regulates cell proliferation and transforming growth factor β-induced epithelial to mesenchymal transition through modulation of integrin β1 stability. Cell Signal. 24:2132–2142. 2012. View Article : Google Scholar : PubMed/NCBI
12	Aigner S, Sthoeger ZM, Fogel M, Weber E, Zarn J, Ruppert M, Zeller Y, Vestweber D, Stahel R, Sammar M, et al: CD24, a mucin-type glycoprotein, is a ligand for P-selectin on human tumor cells. Blood. 89:3385–3395. 1997.PubMed/NCBI
13	Sammar M, Aigner S and Altevogt P: Heat-stable antigen (mouse CD24) in the brain: Dual but distinct interaction with P-selectin and L1. Biochim Biophys Acta. 1337:287–294. 1997. View Article : Google Scholar : PubMed/NCBI
14	King JB, von Furstenberg RJ, Smith BJ, McNaughton KK, Galanko JA and Henning SJ: CD24 can be used to isolate Lgr5⁺ putative colonic epithelial stem cells in mice. Am J Physiol Gastrointest Liver Physiol. 303:G443–G452. 2012. View Article : Google Scholar : PubMed/NCBI
15	Deng J, Gao G, Wang L, Wang T, Yu J and Zhao Z: CD24 expression as a marker for predicting clinical outcome in human gliomas. J Biomed Biotechnol. 2012:5171722012. View Article : Google Scholar : PubMed/NCBI
16	Shi Y, Gong HL, Zhou L, Tian J and Wang Y: CD24: A novel cancer biomarker in laryngeal squamous cell carcinoma. ORL J Otorhinolaryngol Relat Spec. 74:78–85. 2012. View Article : Google Scholar : PubMed/NCBI
17	Kristiansen G, Schlüns K, Yongwei Y, Denkert C, Dietel M and Petersen I: CD24 is an independent prognostic marker of survival in nonsmall cell lung cancer patients. Br J Cancer. 88:231–236. 2003. View Article : Google Scholar : PubMed/NCBI
18	Kristiansen G, Winzer KJ, Mayordomo E, Bellach J, Schlüns K, Denkert C, Dahl E, Pilarsky C, Altevogt P, Guski H, et al: CD24 expression is a new prognostic marker in breast cancer. Clin Cancer Res. 9:4906–4913. 2003.PubMed/NCBI
19	Lee HJ, Kim DI, Kwak C, Ku JH and Moon KC: Expression of CD24 in clear cell renal cell carcinoma and its prognostic significance. Urology. 72:603–607. 2008. View Article : Google Scholar : PubMed/NCBI
20	Su N, Peng L, Xia B, Zhao Y, Xu A, Wang J, Wang X and Jiang B: Lyn is involved in CD24-induced ERK1/2 activation in colorectal cancer. Mol Cancer. 11:432012. View Article : Google Scholar : PubMed/NCBI
21	Liu C, Zheng S, Shen H, Xu K, Chen J, Li H, Xu Y, Xu A, Chen B, Kaku H, et al: Clinical significance of CD24 as a predictor of bladder cancer recurrence. Oncol Lett. 6:96–100. 2013.PubMed/NCBI
22	Zhu J, Zhang G and Lu H: CD24, COX-2, and p53 in epithelial ovarian cancer and its clinical significance. Front Biosci (Elite Ed). 4:2745–2751. 2012.PubMed/NCBI
23	Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF and Simeone DM: Identification of pancreatic cancer stem cells. Cancer Res. 67:1030–1037. 2007. View Article : Google Scholar : PubMed/NCBI
24	Gao MQ, Choi YP, Kang S, Youn JH and Cho NH: CD24⁺ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells. Oncogene. 29:2672–2680. 2010. View Article : Google Scholar : PubMed/NCBI
25	Kim KH, Choi JS, Kim JM, Choi YL, Shin YK, Lee HC, Seong IO, Kim BK, Chae SW and Kim SH: Enhanced CD24 expression in endometrial carcinoma and its expression pattern in normal and hyperplastic endometrium. Histol Histopathol. 24:309–316. 2009.PubMed/NCBI
26	Taylor MA, Parvani JG and Schiemann WP: The pathophysiology of epithelial-mesenchymal transition induced by transforming growth factor-beta in normal and malignant mammary epithelial cells. J Mammary Gland Biol Neoplasia. 15:169–190. 2010. View Article : Google Scholar : PubMed/NCBI
27	Zavadil J and Böttinger EP: TGF-beta and epithelial-to-mesenchymal transitions. Oncogene. 24:5764–5774. 2005. View Article : Google Scholar : PubMed/NCBI
28	Lee YH, Albig AR, Regner M, Schiemann BJ and Schiemann WP: Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and enhances EMT induced by TGF-beta in mammary epithelial cells via a MMP-dependent mechanism. Carcinogenesis. 29:2243–2251. 2008. View Article : Google Scholar : PubMed/NCBI
29	Miettinen PJ, Ebner R, Lopez AR and Derynck R: TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: Involvement of type I receptors. J Cell Biol. 127:2021–2036. 1994. View Article : Google Scholar : PubMed/NCBI
30	Jiang J, Tang YL and Liang XH: EMT: A new vision of hypoxia promoting cancer progression. Cancer Biol Ther. 11:714–723. 2011. View Article : Google Scholar : PubMed/NCBI
31	Bao B, Wang Z, Ali S, Kong D, Banerjee S, Ahmad A, Li Y, Azmi AS, Miele L and Sarkar FH: Over-expression of FoxM1 leads to epithelial-mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells. J Cell Biochem. 112:2296–2306. 2011. View Article : Google Scholar : PubMed/NCBI
32	Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, et al: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 133:704–715. 2008. View Article : Google Scholar : PubMed/NCBI
33	Reya T, Morrison SJ, Clarke MF and Weissman IL: Stem cells, cancer, and cancer stem cells. Nature. 414:105–111. 2001. View Article : Google Scholar : PubMed/NCBI
34	Roszkowski P, Wronkowski Z, Szamborski J and Romejko M: Evaluation of selected prognostic factors in ovarian cancer. Eur J Gynaecol Oncol. 14 Suppl:140–145. 1993.PubMed/NCBI
35	Kristiansen G, Denkert C, Schlüns K, Dahl E, Pilarsky C and Hauptmann S: CD24 is expressed in ovarian cancer and is a new independent prognostic marker of patient survival. Am J Pathol. 161:1215–1221. 2002. View Article : Google Scholar : PubMed/NCBI
36	Surowiak P, Materna V, Kaplenko I, Spaczynski M, Dietel M, Kristiansen G, Lage H and Zabel M: Unfavorable prognostic value of CD24 expression in sections from primary and relapsed ovarian cancer tissue. Int J Gynecol Cancer. 16:515–521. 2006. View Article : Google Scholar : PubMed/NCBI
37	Grünert S, Jechlinger M and Beug H: Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol. 4:657–665. 2003. View Article : Google Scholar : PubMed/NCBI
38	Takai M, Terai Y, Kawaguchi H, Ashihara K, Fujiwara S, Tanaka T, Tsunetoh S, Tanaka Y, Sasaki H, Kanemura M, et al: The EMT (epithelial-mesenchymal-transition)-related protein expression indicates the metastatic status and prognosis in patients with ovarian cancer. J Ovarian Res. 7:762014. View Article : Google Scholar : PubMed/NCBI
39	Hollier BG, Tinnirello AA, Werden SJ, Evans KW, Taube JH, Sarkar TR, Sphyris N, Shariati M, Kumar SV, Battula VL, et al: FOXC2 expression links epithelial-mesenchymal transition and stem cell properties in breast cancer. Cancer Res. 73:1981–1992. 2013. View Article : Google Scholar : PubMed/NCBI
40	Iwatsuki M, Mimori K, Yokobori T, Ishi H, Beppu T, Nakamori S, Baba H and Mori M: Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Sci. 101:293–299. 2010. View Article : Google Scholar : PubMed/NCBI
41	Lee TK, Castilho A, Cheung VC, Tang KH, Ma S and Ng IO: CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell. 9:50–63. 2011. View Article : Google Scholar : PubMed/NCBI
42	Yeung TM, Gandhi SC, Wilding JL, Muschel R and Bodmer WF: Cancer stem cells from colorectal cancer-derived cell lines. Proc Natl Acad Sci USA. 107:pp. 3722–3727. 2010; View Article : Google Scholar : PubMed/NCBI