Abstract
Ovarian cancer is the major cause of mortality due to late stage diagnoses and lower survival rates, and the mechanism of cancer progression is not completely understood. Thus, exploring the regulatory factors of ovarian cancer proliferation and metastasis is urgent. JAG1 expression in KOV3 and OVCA433 cells was detected by qPCR and western blot. MTT and Transwell assays were used to determine cell proliferation and metastasis. The tumor spheres formation assay, DOX, and Cisplatin administrations were performed to assess JAG1-induced stemness and chemoresistance. ChIP assay was used to verify the direct binding of GATA1 on JAG1 promoter. Ovarian cancer cells have higher JAG1 expression, which turns on Notch signaling and promotes cell proliferation, migration, invasion, stemness, and the resistance of chemotherapy. While knockdown JAG1 dramatically suppressed the ovarian cancer progression, GATA1 is the transcriptional factor of JAG1 in ovarian cells, knockdown JAG1 can inhibit GATA1-induced Notch activation and cell proliferation. This study demonstrates that JAG1, acting as an oncogenic gene, plays an important role in ovarian cancer progression and chemoresistance. Targeting GATA1/JAG1/Notch pathway may provide a novel strategy for ovarian cancer treatment.
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References
Bettinsoli P, Ferrari-Toninelli G, Bonini SA, Prandelli C, Memo M (2017) Notch ligand Delta-like 1 as a novel molecular target in childhood neuroblastoma. BMC Cancer 17:352. https://doi.org/10.1186/s12885-017-3340-3
Borggrefe T, Oswald F (2009) The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci 66:1631–1646. https://doi.org/10.1007/s00018-009-8668-7
Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7:678–689. https://doi.org/10.1038/nrm2009
Chillakuri CR, Sheppard D, Ilagan MX, Holt LR, Abbott F, Liang S, Kopan R, Handford PA, Lea SM (2013) Structural analysis uncovers lipid-binding properties of Notch ligands. Cell Rep 5:861–867. https://doi.org/10.1016/j.celrep.2013.10.029
Czemerska M, Pluta A, Szmigielska-Kaplon A, Wawrzyniak E, Cebula-Obrzut B, Medra A, Smolewski P, Robak T, Wierzbowska A (2015) Jagged-1: a new promising factor associated with favorable prognosis in patients with acute myeloid leukemia. Leuk Lymphoma 56:401–406. https://doi.org/10.3109/10428194.2014.917638
D'Souza B, Miyamoto A, Weinmaster G (2008) The many facets of Notch ligands. Oncogene 27:5148–5167. https://doi.org/10.1038/onc.2008.229
Dvorankova B et al (2017) Intercellular crosstalk in human malignant melanoma. Protoplasma 254:1143–1150. https://doi.org/10.1007/s00709-016-1038-z
Espinoza I, Pochampally R, Xing F, Watabe K, Miele L (2013) Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. Onco Targets Ther 6:1249–1259. https://doi.org/10.2147/OTT.S36162
Guo L, Zhang P, Chen Z, Xia H, Li S, Zhang Y, Kobberup S, Zou W, Lin JD (2017) Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression. J Clin Invest 127:4449–4461. https://doi.org/10.1172/JCI96324
Jubb AM, Browning L, Campo L, Turley H, Steers G, Thurston G, Harris AL, Ansorge O (2012) Expression of vascular Notch ligands Delta-like 4 and Jagged-1 in glioblastoma. Histopathology 60:740–747. https://doi.org/10.1111/j.1365-2559.2011.04138.x
Korkaya H, Wicha MS (2007) Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs 21:299–310. https://doi.org/10.2165/00063030-200721050-00002
Leong KG, Niessen K, Kulic I, Raouf A, Eaves C, Pollet I, Karsan A (2007) Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med 204:2935–2948. https://doi.org/10.1084/jem.20071082
Li D, Masiero M, Banham AH, Harris AL (2014) The notch ligand JAGGED1 as a target for anti-tumor therapy. Front Oncol 4:254. https://doi.org/10.3389/fonc.2014.00254
Lin JT, Chen MK, Yeh KT, Chang CS, Chang TH, Lin CY, Wu YC, Su BW, Lee KD, Chang PJ (2010) Association of high levels of Jagged-1 and Notch-1 expression with poor prognosis in head and neck cancer. Ann Surg Oncol 17:2976–2983. https://doi.org/10.1245/s10434-010-1118-9
Lu J, Ye X, Fan F, Xia L, Bhattacharya R, Bellister S, Tozzi F, Sceusi E, Zhou Y, Tachibana I, Maru DM, Hawke DH, Rak J, Mani SA, Zweidler-McKay P, Ellis LM (2013) Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell 23:171–185. https://doi.org/10.1016/j.ccr.2012.12.021
Matulonis UA, Sood AK, Fallowfield L, Howitt BE, Sehouli J, Karlan BY (2016) Ovarian cancer. Nat Rev Dis Primers 2:16061. https://doi.org/10.1038/nrdp.2016.61
Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, Fabbro M, Ledermann JA, Lorusso D, Vergote I, Ben-Baruch NE, Marth C, Mądry R, Christensen RD, Berek JS, Dørum A, Tinker AV, du Bois A, González-Martín A, Follana P, Benigno B, Rosenberg P, Gilbert L, Rimel BJ, Buscema J, Balser JP, Agarwal S, Matulonis UA, ENGOT-OV16/NOVA Investigators (2016) Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 375:2154–2164. https://doi.org/10.1056/NEJMoa1611310
Nelson JD, Denisenko O, Bomsztyk K (2006) Protocol for the fast chromatin immunoprecipitation (ChIP) method. Nat Protoc 1:179–185. https://doi.org/10.1038/nprot.2006.27
Nishina S, Shiraha H, Nakanishi Y, Tanaka S, Matsubara M, Takaoka N, Uemura M, Horiguchi S, Kataoka J, Iwamuro M, Yagi T, Yamamoto K (2011) Restored expression of the tumor suppressor gene RUNX3 reduces cancer stem cells in hepatocellular carcinoma by suppressing Jagged1-Notch signaling. Oncol Rep 26:523–531. https://doi.org/10.3892/or.2011.1336
Reid BM, Permuth JB, Sellers TA (2017) Epidemiology of ovarian cancer: a review. Cancer Biol Med 14:9–32. https://doi.org/10.20892/j.issn.2095-3941.2016.0084
Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M, Ceccarelli C, Santini D, Paterini P, Marcu KB, Chieco P, Bonafè M (2007) IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 117:3988–4002. https://doi.org/10.1172/JCI32533
Sethi N, Dai X, Winter CG, Kang Y (2011) Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 19:192–205. https://doi.org/10.1016/j.ccr.2010.12.022
Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29:4741–4751. https://doi.org/10.1038/onc.2010.215
Smolarkiewicz M, Skrzypczak T, Wojtaszek P (2013) The very many faces of presenilins and the gamma-secretase complex. Protoplasma 250:997–1011. https://doi.org/10.1007/s00709-013-0494-y
Sun HW, Wu C, Tan HY, Wang QS (2012) Combination DLL4 with Jagged1-siRNA can enhance inhibition of the proliferation and invasiveness activity of human gastric carcinoma by Notch1/VEGF pathway. Hepatogastroenterology 59:924–929. https://doi.org/10.5754/hge11484
Torre LA, Trabert B, DeSantis C, Miller KD, Samimi G, Runowicz CD, Gaudet MM, Jemal A, Siegel RL (2018) Ovarian cancer statistics, 2018. CA Cancer J Clin 68:284–296. https://doi.org/10.3322/caac.21456
van Driel WJ, Koole SN, Sikorska K, Schagen van Leeuwen J, Schreuder HWR, Hermans RHM, de Hingh IHJT, van der Velden J, Arts HJ, Massuger LFAG, Aalbers AGJ, Verwaal VJ, Kieffer JM, van de Vijver K, van Tinteren H, Aaronson NK, Sonke GS (2018) Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med 378:230–240. https://doi.org/10.1056/NEJMoa1708618
Wang Z, Li Y, Kong D, Banerjee S, Ahmad A, Azmi AS, Ali S, Abbruzzese JL, Gallick GE, Sarkar FH (2009) Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res 69:2400–2407. https://doi.org/10.1158/0008-5472.CAN-08-4312
Whiteman P, de Madrid BH, Taylor P, Li D, Heslop R, Viticheep N, Tan JZ, Shimizu H, Callaghan J, Masiero M, Li JL, Banham AH, Harris AL, Lea SM, Redfield C, Baron M, Handford PA (2013) Molecular basis for Jagged-1/Serrate ligand recognition by the Notch receptor. J Biol Chem 288:7305–7312. https://doi.org/10.1074/jbc.M112.428854
Yamamoto M, Taguchi Y, Ito-Kureha T, Semba K, Yamaguchi N, Inoue J (2013) NF-kappaB non-cell-autonomously regulates cancer stem cell populations in the basal-like breast cancer subtype. Nat Commun 4:2299. https://doi.org/10.1038/ncomms3299
Zhang P, Yao Q, Lu L, Li Y, Chen PJ, Duan C (2014) Hypoxia-inducible factor 3 is an oxygen-dependent transcription activator and regulates a distinct transcriptional response to hypoxia. Cell Rep 6:1110–1121. https://doi.org/10.1016/j.celrep.2014.02.011
Zheng H, Kang Y (2014) Multilayer control of the EMT master regulators. Oncogene 33:1755–1763. https://doi.org/10.1038/onc.2013.128
Zhu TS, Costello MA, Talsma CE, Flack CG, Crowley JG, Hamm LL, He X, Hervey-Jumper SL, Heth JA, Muraszko KM, DiMeco F, Vescovi AL, Fan X (2011) Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. Cancer Res 71:6061–6072. https://doi.org/10.1158/0008-5472.CAN-10-4269
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Liu, Z., Zhu, Y., Li, F. et al. GATA1-regulated JAG1 promotes ovarian cancer progression by activating Notch signal pathway. Protoplasma 257, 901–910 (2020). https://doi.org/10.1007/s00709-019-01477-w
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DOI: https://doi.org/10.1007/s00709-019-01477-w