Chemokine CCL20 promotes the paclitaxel resistance of CD44<sup>+</sup>CD117<sup>+</sup> cells via the Notch1 signaling pathway in ovarian cancer

Chen,Min; Su,Juan; Feng,Chunmei; Liu,Ying; Zhao,Li; Tian,Yongjie

doi:10.3892/mmr.2021.12274

Chemokine CCL20 promotes the paclitaxel resistance of CD44⁺CD117⁺ cells via the Notch1 signaling pathway in ovarian cancer

Authors:
- Min Chen
- Juan Su
- Chunmei Feng
- Ying Liu
- Li Zhao
- Yongjie Tian
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Affiliations: Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, P.R. China, Department of Obstetrics and Gynecology, Taian City Central Hospital, Taian, Shandong 271000, P.R. China
Published online on: July 6, 2021 https://doi.org/10.3892/mmr.2021.12274
Article Number: 635
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Studies have found that C‑C motif chemokine ligand 20 (CCL20)/C‑C motif chemokine receptor 6 (CCR6)/notch receptor 1 (Notch1) signaling serves an important role in various diseases, but its role and mechanism in ovarian cancer remains to be elucidated. The aim of the present study was to investigate the underlying mechanism of CCL20/CCR6/Notch1 signaling in paclitaxel (PTX) resistance of a CD44⁺CD117⁺ subgroup of cells in ovarian cancer. The CD44⁺CD117⁺ cells were isolated from SKOV3 cells, followed by determination of the PTX resistance and the CCR6/Notch1 axis. Notch1 was silenced in the CD44⁺CD117⁺ subgroup and these cells were treated with CCL20, followed by examination of PTX resistance and the CCR6/Notch1 axis. Furthermore, in nude mice, CD44⁺CD117⁺ and CD44^‑CD117^‑ cells were used to establish the xenograft model and cells were treated with PTX and/or CCL20, followed by proliferation, apoptosis, reactive oxygen species (ROS) and mechanism analyses. Higher expression levels of Oct4, CCR6, Notch1 and ATP binding cassette subfamily G member 1 (ABCG1), increased sphere formation ability, IC₅₀ and proliferative ability, as well as lower ROS levels and apoptosis were observed in CD44⁺CD117⁺ cells compared with the CD44^‑CD117^‑ cells. It was found that CCL20 could significantly increase the expression levels of Oct4, CCR6, Notch1 and ABCG1, enhance the IC₅₀, sphere formation ability and proliferation, as well as decrease the ROS and apoptosis levels in the CD44⁺CD117⁺ cells. However, Notch1 knockdown could markedly reverse these changes. Moreover, CCL20 could significantly increase the proliferation and expression levels of Oct4, CCR6, Notch1 and ABCG1 in the CD44⁺CD117⁺ groups compared with the CD44^‑CD117^‑ groups. After treatment with PTX, apoptosis and ROS levels were decreased in the CD44⁺CD117⁺ groups compared with the CD44^‑CD117^‑ groups. Collectively, the present results demonstrated that, via the Notch1 pathway, CCL20/CCR6 may promote the stemness and PTX resistance of CD44⁺CD117⁺ cells in ovarian cancer.

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1	Vafadar A, Shabaninejad Z, Movahedpour A, Fallahi F, Taghavipour M, Ghasemi Y, Akbari M, Shafiee A, Hajighadimi S, Moradizarmehri S, et al: Quercetin and cancer: New insights into its therapeutic effects on ovarian cancer cells. Cell Biosci. 10:322020. View Article : Google Scholar : PubMed/NCBI
2	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
3	Momenimovahed Z, Tiznobaik A, Taheri S and Salehiniya H: Ovarian cancer in the world: Epidemiology and risk factors. Int J Womens Health. 11:287–299. 2019. View Article : Google Scholar : PubMed/NCBI
4	Stewart C, Ralyea C and Lockwood S: Ovarian cancer: An integrated review. Semin Oncol Nurs. 35:151–156. 2019. View Article : Google Scholar : PubMed/NCBI
5	Norouzi-Barough L, Sarookhani MR, Sharifi M, Moghbelinejad S, Jangjoo S and Salehi R: Molecular mechanisms of drug resistance in ovarian cancer. J Cell Physiol. 233:4546–4562. 2018. View Article : Google Scholar : PubMed/NCBI
6	Damia G and Broggini M: Platinum resistance in ovarian cancer: Role of DNA repair. Cancers (Basel). 11:1192019. View Article : Google Scholar : PubMed/NCBI
7	Pagotto A, Pilotto G, Mazzoldi EL, Nicoletto MO, Frezzini S, Pastò A and Amadori A: Autophagy inhibition reduces chemoresistance and tumorigenic potential of human ovarian cancer stem cells. Cell Death Dis. 8:e29432017. View Article : Google Scholar : PubMed/NCBI
8	Pieterse Z, Amaya-Padilla MA, Singomat T, Binju M, Madjid BD, Yu Y and Kaur P: Ovarian cancer stem cells and their role in drug resistance. Int J Biochem Cell Biol. 106:117–126. 2019. View Article : Google Scholar : PubMed/NCBI
9	Klemba A, Purzycka-Olewiecka JK, Wcisło G, Czarnecka AM, Lewicki S, Lesyng B, Szczylik C and Kieda C: Surface markers of cancer stem-like cells of ovarian cancer and their clinical relevance. Contemp Oncol (Pozn). 22:48–55. 2018.PubMed/NCBI
10	Chung H, Kim YH, Kwon M, Shin SJ, Kwon SH, Cha SD and Cho CH: The effect of salinomycin on ovarian cancer stem-like cells. Obstet Gynecol Sci. 59:261–268. 2016. View Article : Google Scholar : PubMed/NCBI
11	Zhang S, Balch C, Chan MW, Lai HC, Matei D, Schilder JM, Yan PS, Huang TH and Nephew KP: Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 68:4311–4320. 2008. View Article : Google Scholar : PubMed/NCBI
12	Wintzell M, Löfstedt L, Johansson J, Pedersen AB, Fuxe J and Shoshan M: Repeated cisplatin treatment can lead to a multiresistant tumor cell population with stem cell features and sensitivity to 3-bromopyruvate. Cancer Biol Ther. 13:1454–1462. 2012. View Article : Google Scholar : PubMed/NCBI
13	Chen W, Qin Y and Liu S: CCL20 signaling in the tumor microenvironment. Adv Exp Med Biol. 1231:53–65. 2020. View Article : Google Scholar : PubMed/NCBI
14	Su S, Sun X, Zhang Q, Zhang Z and Chen J: CCL20 promotes ovarian cancer chemotherapy resistance by regulating ABCB1 expression. Cell Struct Funct. 44:21–28. 2019. View Article : Google Scholar : PubMed/NCBI
15	Kadomoto S, Izumi K and Mizokami A: The CCL20-CCR6 axis in cancer progression. Int J Mol Sci. 21:51862020. View Article : Google Scholar : PubMed/NCBI
16	Liu W, Wang W, Wang X, Xu C, Zhang N and Di W: Cisplatin-stimulated macrophages promote ovarian cancer migration via the CCL20-CCR6 axis. Cancer Lett. 472:59–69. 2020. View Article : Google Scholar : PubMed/NCBI
17	Yi L, Zhou X, Li T, Liu P, Hai L, Tong L, Ma H, Tao Z, Xie Y, Zhang C, et al: Notch1 signaling pathway promotes invasion, self-renewal and growth of glioma initiating cells via modulating chemokine system CXCL12/CXCR4. J Exp Clin Cancer Res. 38:3392019. View Article : Google Scholar : PubMed/NCBI
18	Gharaibeh L, Elmadany N, Alwosaibai K and Alshaer W: Notch1 in cancer therapy: Possible clinical implications and challenges. Mol Pharmacol. 98:559–576. 2020. View Article : Google Scholar : PubMed/NCBI
19	Sanchez-Martin M and Ferrando A: The NOTCH1-MYC highway toward T-cell acute lymphoblastic leukemia. Blood. 129:1124–1133. 2017. View Article : Google Scholar : PubMed/NCBI
20	Luo Y, Kishi S, Sasaki T, Ohmori H, Fujiwara-Tani R, Mori S, Goto K, Nishiguchi Y, Mori T, Kawahara I, et al: Targeting claudin-4 enhances chemosensitivity in breast cancer. Cancer Sci. 111:1840–1850. 2020. View Article : Google Scholar : PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
22	Ning Y, Feng W, Cao X, Ren K, Quan M, Chen A, Xu C, Qiu Y, Cao J, Li X and Luo X: Genistein inhibits stemness of SKOV3 cells induced by macrophages co-cultured with ovarian cancer stem-like cells through IL-8/STAT3 axis. J Exp Clin Cancer Res. 38:192019. View Article : Google Scholar : PubMed/NCBI
23	Martincuks A, Li PC, Zhao Q, Zhang C, Li YJ, Yu H and Rodriguez-Rodriguez L: CD44 in ovarian cancer progression and therapy resistance-A critical role for STAT3. Front Oncol. 10:5896012020. View Article : Google Scholar : PubMed/NCBI
24	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
25	Zhang R, Zhang P, Wang H, Hou D, Li W, Xiao G and Li C: Inhibitory effects of metformin at low concentration on epithelial-mesenchymal transition of CD44(+)CD117(+) ovarian cancer stem cells. Stem Cell Res Ther. 6:2622015. View Article : Google Scholar : PubMed/NCBI
26	Cheng W, Liu T, Wan X, Gao Y and Wang H: MicroRNA-199a targets CD44 to suppress the tumorigenicity and multidrug resistance of ovarian cancer-initiating cells. FEBS J. 279:2047–2059. 2012. View Article : Google Scholar : PubMed/NCBI
27	Yang B, Yan X, Liu L, Jiang C and Hou S: Overexpression of the cancer stem cell marker CD117 predicts poor prognosis in epithelial ovarian cancer patients: Evidence from meta-analysis. Onco Targets Ther. 10:2951–2961. 2017. View Article : Google Scholar : PubMed/NCBI
28	Kleih M, Böpple K, Dong M, Gaißler A, Heine S, Olayioye MA, Aulitzky WE and Essmann F: Direct impact of cisplatin on mitochondria induces ROS production that dictates cell fate of ovarian cancer cells. Cell Death Dis. 10:8512019. View Article : Google Scholar : PubMed/NCBI
29	Moloney JN and Cotter TG: ROS signalling in the biology of cancer. Semin Cell Dev Biol. 80:50–64. 2018. View Article : Google Scholar : PubMed/NCBI
30	Zhang XP, Hu ZJ, Meng AH, Duan GC, Zhao QT and Yang J: Role of CCL20/CCR6 and the ERK signaling pathway in lung adenocarcinoma. Oncol Lett. 14:8183–8189. 2017.PubMed/NCBI
31	Frick VO, Rubie C, Keilholz U and Ghadjar P: Chemokine/chemokine receptor pair CCL20/CCR6 in human colorectal malignancy: An overview. World J Gastroenterol. 22:833–841. 2016. View Article : Google Scholar : PubMed/NCBI
32	Zeng W, Chang H, Ma M and Li Y: CCL20/CCR6 promotes the invasion and migration of thyroid cancer cells via NF-kappa B signaling-induced MMP-3 production. Exp Mol Pathol. 97:184–190. 2014. View Article : Google Scholar : PubMed/NCBI
33	Thapa S and Bhusal K: SUN-545 A rare case of resistance to thyroid hormone due to novel mutation in THRB gene mistreated as hyperthyroidism. J Endocr Soc. 3 (Suppl 1):SUN–545. 2019. View Article : Google Scholar
34	Ranasinghe R and Eri R: Modulation of the CCR6-CCL20 axis: A potential therapeutic target in inflammation and cancer. Medicina (Kaunas). 54:882018. View Article : Google Scholar : PubMed/NCBI
35	Liu W, Wang W, Zhang N and Di W: The role of CCL20-CCR6 axis in ovarian cancer metastasis. Onco Targets Ther. 13:12739–12750. 2020. View Article : Google Scholar : PubMed/NCBI
36	Zhang J, Yu K, Han X, Zhen L, Liu M, Zhang X, Ren Y and Shi J: Paeoniflorin influences breast cancer cell proliferation and invasion via inhibition of the Notch-1 signaling pathway. Mol Med Rep. 17:1321–1325. 2018.PubMed/NCBI
37	Zhang Z, Han H, Rong Y, Zhu K, Zhu Z, Tang Z, Xiong C and Tao J: Hypoxia potentiates gemcitabine-induced stemness in pancreatic cancer cells through AKT/Notch1 signaling. J Exp Clin Cancer Res. 37:2912018. View Article : Google Scholar : PubMed/NCBI
38	Wang X, Wang R, Bai S, Xiong S, Li Y, Liu M, Zhao Z, Wang Y, Zhao Y, Chen W, et al: Musashi2 contributes to the maintenance of CD44v6+ liver cancer stem cells via notch1 signaling pathway. J Exp Clin Canc Res. 38:5052019. View Article : Google Scholar : PubMed/NCBI
39	Seo EJ, Kim DK, Jang IH, Choi EJ, Shin SH, Lee SI, Kwon SM, Kim KH, Suh DS and Kim JH: Hypoxia-NOTCH1-SOX2 signaling is important for maintaining cancer stem cells in ovarian cancer. Oncotarget. 7:55624–55638. 2016. View Article : Google Scholar : PubMed/NCBI
40	Kang HG, Kim DH, Kim SJ, Cho Y, Jung J, Jang W and Chun KH: Galectin-3 supports stemness in ovarian cancer stem cells by activation of the Notch1 intracellular domain. Oncotarget. 7:682292016. View Article : Google Scholar : PubMed/NCBI