{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T20:02:59Z","timestamp":1785355379219,"version":"3.55.0"},"reference-count":48,"publisher":"Begell House","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Crit Rev Eukaryot Gene Expr"],"published-print":{"date-parts":[[2026]]},"abstract":"<p>&lt;b&gt;Background:&lt;\/b&gt; Esophageal squamous cell carcinoma (ESCC) has a poor prognosis due to its aggressiveness and chemoresistance, necessitating novel therapeutic strategies. Dihydroartemisinin (DHA), an artemisinin derivative, exhibits broad anticancer activity, but its mechanism in ESCC remains incompletely understood.\n\n&lt;b&gt;Methods:&lt;\/b&gt; Transcriptomic sequencing identified differentially expressed genes upon DHA treatment. The regulation of COX-2 by DHA was validated via RT-qPCR and Western blot. Gain- and loss-of-function assays assessed COX-2 and Sp1 effects on ESCC proliferation and migration. Dual-luciferase reporter assays confirmed Sp1-driven COX-2 transcription. ROS levels and MAPK pathway protein expression were measured by flow cytometry and Western blot, respectively. A xenograft model evaluated in vivo effects of Sp1 overexpression and DHA.\n\n&lt;b&gt;Results:&lt;\/b&gt; DHA downregulated COX-2 in a time- and dose-dependent manner, inhibiting ESCC cell proliferation and migration. Sp1 directly bound the COX-2 promoter and positively regulated its expression, thereby promoting malignant phenotypes. DHA triggered ROS accumulation and downregulated the protein levels of MAPK (ERK\/MSK), Sp1, and COX-2. Both NAC (an antioxidant) and Sp1 overexpression reversed these effects. In vivo, DHA significantly suppressed tumor growth via the Sp1\/COX-2 axis without detectable toxicity.\n\n&lt;b&gt;Conclusion:&lt;\/b&gt; This study establishes that DHA inhibits ESCC proliferation and metastasis through the ROS-MAPK(ERK\/MSK)-Sp1-COX-2 axis, highlighting DHA as a promising repurposed agent and identifying Sp1\/COX-2 as novel therapeutic targets for ESCC.<\/p>","DOI":"10.1615\/critreveukaryotgeneexpr.2026064579","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T14:44:04Z","timestamp":1781621044000},"page":"59-77","source":"Crossref","is-referenced-by-count":0,"title":["Dihydroartemisinin Suppresses Esophageal Squamous Cell Carcinoma by Downregulating COX-2 through the ROS\/MAPK\/Sp1 Pathway"],"prefix":"10.1615","volume":"36","author":[{"given":"Chongbo","family":"Liao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyao","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maoju","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man\u00a0","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowu","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hebin","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"613","reference":[{"key":"1","doi-asserted-by":"crossref","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-63.","DOI":"10.3322\/caac.21834"},{"key":"2","doi-asserted-by":"crossref","unstructured":"Mbatha SZ, Maphosho T, Ramali D, Damane B, Nevhungoni P, Mc-Cabe M, Mosoane B, Hull R, Dlamini Z. Human papillomavirus, human immunodeficiency virus, and esophageal squamous cell carcinoma in South Africa: A study of prevalence, co-infection, and risk factors. Front Oncol. 2025;15:1634565.","DOI":"10.3389\/fonc.2025.1634565"},{"key":"3","doi-asserted-by":"crossref","unstructured":"Han B, Zheng R, Zeng H, Wang S, Sun K, Chen R, Li L, Wei W, He J. Cancer incidence and mortality in China, 2022. J Natl Cancer Cent. 2024;4(1):47-53.","DOI":"10.1016\/j.jncc.2024.01.006"},{"key":"4","doi-asserted-by":"crossref","unstructured":"Li J, Xu J, Zheng Y, Gao Y, He S, Li H, Zou K, Li N, Tian J, Chen W, He J. Esophageal cancer: Epidemiology, risk factors and screening. Chin J Cancer Res. 2021;33(5):535-47.","DOI":"10.21147\/j.issn.1000-9604.2021.05.01"},{"key":"5","doi-asserted-by":"crossref","unstructured":"Hamai Y, Hihara J, Emi M, Furukawa T, Ibuki Y, Yamakita I, Kurokawa T, Okada M. Treatment outcomes and prognostic factors after recurrence of esophageal squamous cell carcinoma. World J Surg. 2018;42(7):2190-8.","DOI":"10.1007\/s00268-017-4430-8"},{"key":"6","doi-asserted-by":"crossref","unstructured":"Klayman DL. Qinghaosu (artemisinin): An antimalarial drug from China. Science. 1985;228(4703):1049-55.","DOI":"10.1126\/science.3887571"},{"key":"7","doi-asserted-by":"crossref","unstructured":"Dai X, Zhang X, Chen W, Chen Y, Zhang Q, Mo S, Lu J. Dihydroartemisinin: A potential natural anticancer drug. Int J Biol Sci. 2021;17(2):603-22.","DOI":"10.7150\/ijbs.50364"},{"key":"8","doi-asserted-by":"crossref","unstructured":"Zhu L, Chen X, Zhu Y, Qin J, Niu T, Ding Y, Xiao Y, Jiang Y, Liu K, Lu J, Yang W, Qiao Y, Jin G, Ma J, Dong Z, Zhao J. Dihydroartemisinin inhibits the proliferation of esophageal squamous cell carcinoma partially by targeting AKT1 and p70S6K. Front Pharmacol. 2020;11:587470.","DOI":"10.3389\/fphar.2020.587470"},{"key":"9","doi-asserted-by":"crossref","unstructured":"Cui J, Jia J. Natural COX-2 inhibitors as promising anti-inflammatory agents: An update. Curr Med Chem. 2021;28(18):3622-46.","DOI":"10.2174\/0929867327999200917150939"},{"key":"10","doi-asserted-by":"crossref","unstructured":"Wang D, Dubois RN. Prostaglandins and cancer. Gut. 2006;55(1):115-22.","DOI":"10.1136\/gut.2004.047100"},{"key":"11","doi-asserted-by":"crossref","unstructured":"Yao C, Narumiya S. Prostaglandin-cytokine crosstalk in chronic inflammation. Br J Pharmacol. 2019;176(3):337-54.","DOI":"10.1111\/bph.14530"},{"key":"12","doi-asserted-by":"crossref","unstructured":"Coupland CA, Naylor-Adamson L, Booth Z, Price TW, Gil HM, Firth G, Avery M, Ahmed Y, Stasiuk GJ, Calaminus SDJ. Platelet zinc status regulates prostaglandin-induced signaling, altering thrombus formation. J Thromb Haemost. 2023;21(9):2545-58.","DOI":"10.1016\/j.jtha.2023.05.008"},{"key":"13","doi-asserted-by":"crossref","unstructured":"Raj V, Bhadauria AS, Singh AK, Kumar U, Rai A, Keshari AK, Kumar P, Kumar D, Maity B, Nath S, Prakash A, Ansari KM, Jat JL, Saha S. Novel 1,3,4-thiadiazoles inhibit colorectal cancer via blockade of IL-6\/COX-2 mediated JAK2\/STAT3 signals as evidenced through data-based mathematical modeling. Cytokine. 2019;118:144-59.","DOI":"10.1016\/j.cyto.2018.03.026"},{"key":"14","doi-asserted-by":"crossref","unstructured":"Gurram B, Zhang S, Li M, Li H, Xie Y, Cui H, Du J, Fan J, Wang J, Peng X. Celecoxib conjugated fluorescent probe for identification and discrimination of cyclooxygenase-2 enzyme in cancer cells. Anal Chem. 2018;90(8):5187-93.","DOI":"10.1021\/acs.analchem.7b05337"},{"key":"15","doi-asserted-by":"crossref","unstructured":"Wang Y, Liu S, Li B, Jiang Y, Zhou X, Chen J, Li M, Ren B, Peng X, Zhou X, Cheng L. Staphylococcus aureus induces COX-2-dependent proliferation and malignant transformation in oral keratinocytes. J Oral Microbiol. 2019;11(1):1643205.","DOI":"10.1080\/20002297.2019.1643205"},{"key":"16","doi-asserted-by":"crossref","unstructured":"Hashemi Goradel N, Najafi M, Salehi E, Farhood B, Mortezaee K. Cyclooxygenase-2 in cancer: A review. J Cell Physiol. 2019;234(5):5683-99.","DOI":"10.1002\/jcp.27411"},{"key":"17","doi-asserted-by":"crossref","unstructured":"Szpirer J, Szpirer C, Riviere M, Levan G, Marynen P, Cassiman JJ, Wiese R, DeLuca HF. The Sp1 transcription factor gene (SP1) and the 1,25-dihydroxyvitamin D3 receptor gene (VDR) are colocalized on human chromosome arm 12q and rat chromosome 7. Genomics. 1991;11(1):168-73.","DOI":"10.1016\/0888-7543(91)90114-T"},{"key":"18","doi-asserted-by":"crossref","unstructured":"Kadonaga JT, Jones KA, Tjian R. Promoter specific activation of RNA polymerase II transcription by Sp1. Trends Biochem Sci. 1986;11:20-3.","DOI":"10.1016\/0968-0004(86)90226-4"},{"key":"19","doi-asserted-by":"crossref","unstructured":"Swift ML, Beishline K, Flashner S, Azizkhan-Clifford J. DSB repair pathway choice is regulated by recruitment of 53BP1 through cell cycle-dependent regulation of Sp1. Cell Rep. 2021;34(11):108840.","DOI":"10.1016\/j.celrep.2021.108840"},{"key":"20","doi-asserted-by":"crossref","unstructured":"Zhong L, Sun Y, Wang C, Liu R, Ru W, Dai W, Xiong T, Zhong A, Li S. SP1 regulates BMSC osteogenic differentiation through the miR-133a-3p\/MAPK3 axis: SP1 regulates osteogenic differentiation of BMSCs. J Orthop Surg Res. 2024;19(1):396.","DOI":"10.1186\/s13018-024-04889-4"},{"key":"21","doi-asserted-by":"crossref","unstructured":"Chen H, Li M, Zhang Y, Song M, Que Y, Wang J, Sun F, Zhu J, Huang J, Liu J, Xu J, Lu S, Zhang Y. AURKB inhibition induces rhabdomyosarcoma apoptosis and ferroptosis through NPM1\/SP1\/ACSL5 axis. JCI Insight. 2025;10(3):e182429.","DOI":"10.1172\/jci.insight.182429"},{"key":"22","doi-asserted-by":"crossref","unstructured":"Lu H, Yuan P, Ma X, Jiang X, Liu S, Ma C, Philipsen S, Zhang Q, Yang J, Xu F, Zhang C, Zhang Y, Zhang W. Angiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1\/Sp3-mediated inhibition of notch signaling in male mice. Nat Commun. 2023;14(1):731.","DOI":"10.1038\/s41467-023-36409-z"},{"key":"23","doi-asserted-by":"crossref","unstructured":"Kim DJ, Iwasaki A, Chien AL, Kang S. UVB-mediated DNA damage induces matrix metalloproteinases to promote photoaging in an AhR- and SP1-dependent manner. JCI Insight. 2022;7(9):e156344.","DOI":"10.1172\/jci.insight.156344"},{"key":"24","doi-asserted-by":"crossref","unstructured":"Lusby R, Demirdizen E, Inayatullah M, Kundu P, Maiques O, Zhang Z, Terp MG, Sanz-Moreno V, Tiwari VK. Pan-cancer drivers of metastasis. Mol Cancer. 2025;24(1):2.","DOI":"10.1186\/s12943-024-02182-w"},{"key":"25","doi-asserted-by":"crossref","unstructured":"Su F, Geng J, Li X, Qiao C, Luo L, Feng J, Dong X, Lv M. SP1 promotes tumor angiogenesis and invasion by activating VEGF expression in an acquired trastuzumabresistant ovarian cancer model. Oncol Rep. 2017;38(5):2677-84.","DOI":"10.3892\/or.2017.5998"},{"key":"26","doi-asserted-by":"crossref","unstructured":"Chiou JT, Lee YC, Huang CH, Wang LJ, Shi YJ, Chang LS. Inhibition of Sp1-mediated survivin and MCL1 expression cooperates with SLC35F2 and myeloperoxidase to modulate YM155 cytotoxicity to human leukemia cells. Biochem Pharmacol. 2021;188:114544.","DOI":"10.1016\/j.bcp.2021.114544"},{"key":"27","doi-asserted-by":"crossref","unstructured":"Xiao X, Chen M, Sang Y, Xue J, Jiang K, Chen Y, Zhang L, Yu S, Lv W, Li Y, Liu R, Xiao H. Methylation-mediated silencing of ATF3 promotes thyroid cancer progression by regulating prognostic genes in the MAPK and PI3K\/AKT pathways. Thyroid. 2023;33(12):1441-54.","DOI":"10.1089\/thy.2023.0157"},{"key":"28","doi-asserted-by":"crossref","unstructured":"Hu C, Huang W, Xiong N, Liu X. SP1-mediated transcriptional activation of PTTG1 regulates the migration and phenotypic switching of aortic vascular smooth muscle cells in aortic dissection through MAPK signaling. Arch Biochem Biophys. 2021;711:109007.","DOI":"10.1016\/j.abb.2021.109007"},{"key":"29","doi-asserted-by":"crossref","unstructured":"Wang Y, Xia Y, Hu K, Zeng M, Zhi C, Lai M, Wu L, Liu S, Zeng S, Huang Z, Ma S, Yuan Z. MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma. Int J Cancer. 2019;145(9):2496-508.","DOI":"10.1002\/ijc.32321"},{"key":"30","doi-asserted-by":"crossref","unstructured":"Lee S, Rauch J, Kolch W. Targeting MAPK signaling in cancer: Mechanisms of drug resistance and sensitivity. Int J Mol Sci. 2020;21(3):1102.","DOI":"10.3390\/ijms21031102"},{"key":"31","doi-asserted-by":"crossref","unstructured":"Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y, Hu LL. ERK\/MAPK signalling pathway and tumorigenesis. Exp Ther Med. 2020;19(3):1997-2007.","DOI":"10.3892\/etm.2020.8454"},{"key":"32","doi-asserted-by":"crossref","unstructured":"Ullah R, Yin Q, Snell AH, Wan L. RAF-MEK-ERK pathway in cancer evolution and treatment. Semin Cancer Biol. 2022;85:123-54.","DOI":"10.1016\/j.semcancer.2021.05.010"},{"key":"33","doi-asserted-by":"crossref","unstructured":"Asl ER, Amini M, Najafi S, Mansoori B, Mokhtarzadeh A, Mohammadi A, Lotfinejad P, Bagheri M, Shirjang S, Lotfi Z, Rasmi Y, Baradaran B. Interplay between MAPK\/ERK signaling pathway and MicroRNAs: A crucial mechanism regulating cancer cell metabolism and tumor progression. Life Sci. 2021;278:119499.","DOI":"10.1016\/j.lfs.2021.119499"},{"key":"34","doi-asserted-by":"crossref","unstructured":"Moloney JN, Cotter TG. ROS signalling in the biology of cancer. Semin Cell Dev Biol. 2018;80:50-64.","DOI":"10.1016\/j.semcdb.2017.05.023"},{"key":"35","doi-asserted-by":"crossref","unstructured":"Cheung EC, Vousden KH. The role of ROS in tumour development and progression. Nat Rev Cancer. 2022;22(5):280-97.","DOI":"10.1038\/s41568-021-00435-0"},{"key":"36","doi-asserted-by":"crossref","unstructured":"Zhang Y, Wang Y, Li Y, Huang C, Xiao X, Zhong Z, Tang J, Lu H, Tang Y, Yang J. Dihydroartemisinin and artesunate inhibit aerobic glycolysis via suppressing c-Myc signaling in non-small cell lung cancer. Biochem Pharmacol. 2022;198:114941.","DOI":"10.1016\/j.bcp.2022.114941"},{"key":"37","doi-asserted-by":"crossref","unstructured":"Hao L, Guo Y, Peng Q, Zhang Z, Ji J, Liu Y, Xue Y, Li C, Zheng K, Shi X. Dihydroartemisinin reduced lipid droplet deposition by YAP1 to promote the anti-PD-1 effect in hepatocellular carcinoma. Phytomedicine. 2022;96:153913.","DOI":"10.1016\/j.phymed.2021.153913"},{"key":"38","doi-asserted-by":"crossref","unstructured":"Jiang M, Wu Y, Qi L, Li L, Song D, Gan J, Li Y, Ling X, Song C. Dihydroartemisinin mediating PKM2-caspase-8\/3-GSDME axis for pyroptosis in esophageal squamous cell carcinoma. Chem Biol Interact. 2021;350:109704.","DOI":"10.1016\/j.cbi.2021.109704"},{"key":"39","doi-asserted-by":"crossref","unstructured":"Yang Y, Zhao Y, Liu L, Zhu W, Jia S, Li X, Li W. The Anti-Apoptotic Role of COX-2 during in vitro infection of human intestinal cell line by Giardia duodenalis and the potential regulators. Infect Immun. 2022;90(3):e0067221.","DOI":"10.1128\/iai.00672-21"},{"key":"40","doi-asserted-by":"crossref","unstructured":"Li Q, Ma Q, Xu L, Gao C, Yao L, Wen J, Yang M, Cheng J, Zhou X, Zou J, Zhong X, Guo X. Human telomerase reverse transcriptase as a therapeutic target of dihydroartemisinin for esophageal squamous cancer. Front Pharmacol. 2021;12:769787.","DOI":"10.3389\/fphar.2021.769787"},{"key":"41","doi-asserted-by":"crossref","unstructured":"Xi P, Ma X, Hu F, Li L, Liu H, Zhou J, Wu W. ROS-Sp1 axis is involved in thermochemotherapy-enhanced sensitivity of pancreatic cancer cells to gemcitabine. Cell Biol Int. 2023;47(11):1825-34.","DOI":"10.1002\/cbin.12073"},{"key":"42","unstructured":"O'Connor L, Gilmour J, Bonifer C. The role of the ubiquitously expressed transcription factor Sp1 in tissue-specific transcriptional regulation and in disease. Yale J Biol Med. 2016;89(4):513-25."},{"key":"43","doi-asserted-by":"crossref","unstructured":"Hang J, Hu H, Huang J, Han T, Zhuo M, Zhou Y, Wang L, Wang Y, Jiao F, Wang L. Sp1 and COX2 expression is positively correlated with a poor prognosis in pancreatic ductal adenocarcinoma. Oncotarget. 2016;7(19):28207-17.","DOI":"10.18632\/oncotarget.8593"},{"key":"44","doi-asserted-by":"crossref","unstructured":"Hu H, Han T, Zhuo M, Wu LL, Yuan C, Wu L, Lei W, Jiao F, Wang LW. Elevated COX-2 Expression promotes angiogenesis through EGFR\/p38-MAPK\/Sp1-dependent signalling in pancreatic cancer. Sci Rep. 2017;7(1):470.","DOI":"10.1038\/s41598-017-00288-4"},{"key":"45","doi-asserted-by":"crossref","unstructured":"Balmanno K, Kidger AM, Byrne DP, Sale MJ, Nassman N, Eyers PA, Cook SJ. ERK1\/2 inhibitors act as monovalent degraders inducing ubiquitylation and proteasome-dependent turnover of ERK2, but not ERK1. Biochem J. 2023;480(9):587-605.","DOI":"10.1042\/BCJ20220598"},{"key":"46","doi-asserted-by":"crossref","unstructured":"Meco M, Giustiniano E, Nisi F, Zulli P, Agosteo E. MAPK, PI3K\/Akt pathways, and GSK-3&#946; activity in severe acute heart failure in intensive care patients: An updated review. J Cardiovasc Dev Dis. 2025;12(7):266.","DOI":"10.3390\/jcdd12070266"},{"key":"47","doi-asserted-by":"crossref","unstructured":"Gao D, Lv Y, Hong F, Wu D, Wang T, Gao G, Lin Z, Yang R, Hu J, He A, Zhang P. Peroxiredoxin 6 maintains mitochondrial homeostasis and promotes tumor progression through ROS\/JNK\/p38 MAPK signaling pathway in multiple myeloma. Sci Rep. 2025;15(1):70.","DOI":"10.1038\/s41598-024-84021-y"},{"key":"48","doi-asserted-by":"crossref","unstructured":"Fan CD, Li Y, Fu XT, Wu QJ, Hou YJ, Yang MF, Sun JY, Fu XY, Zheng ZC, Sun BL. Reversal of beta-amyloid-induced neurotoxicity in PC12 cells by curcumin, the important role of ROS-Mediated Signaling and ERK pathway. Cell Mol Neurobiol. 2017;37(2):211-22.","DOI":"10.1007\/s10571-016-0362-3"}],"container-title":["Critical Reviews in Eukaryotic Gene Expression"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.dl.begellhouse.com\/download\/article\/65b12a3b3d21d071\/CRE-64579.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T19:16:59Z","timestamp":1785352619000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.dl.begellhouse.com\/journals\/6dbf508d3b17c437,320bc5320bccf579,65b12a3b3d21d071.html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":48,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.1615\/critreveukaryotgeneexpr.2026064579","relation":{},"ISSN":["1045-4403"],"issn-type":[{"value":"1045-4403","type":"print"}],"subject":[],"published":{"date-parts":[[2026]]}}}