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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Research Article

JNK2 Promotes Progression of Esophageal Squamous Cell Carcinoma via Inhibiting Axin2

Author(s): Lulu Wang, Meng Guo, Li Gao, Kai Liu, Jiawei Bai and Zhiguo Liu*

Volume 29, Issue 37, 2023

Published on: 08 November, 2023

Page: [2977 - 2987] Pages: 11

DOI: 10.2174/0113816128261624231030110157

Price: $65

Abstract

Introduction: The dysregulation of the c-Jun NH2-terminal kinase (JNK) pathway has been increasingly reported in human malignancies. Aberrant expression of the JNK pathway has also been implicated in the progression of Esophageal Squamous Cell Carcinoma (ESCC). However, the specific role and regulatory mechanisms of JNK2 in ESCC have not been extensively investigated.

Methods: In this study, we examined JNK2 expression in patient samples and performed experiments involving the knockdown and inhibition of the JNK2 in ESCC cell lines.

Results: Higher JNK2 expression was observed in tumor tissues compared to adjacent tissues. JNK2 overexpression was associated with advanced disease stages and poor prognosis. Furthermore, knockdown or inhibition of JNK2 in ESCC cell lines resulted in a decrease in cell proliferation and migration.

Conclusion: Additionally, a significant decrease in the expression of β-catenin and vimentin, along with an increase in the expression of Axin2, was observed upon downregulation of JNK2. Our study provides insight into the role of JNK2 in ESCC and its potential regulatory mechanism, offering a potential therapeutic strategy for ESCC patients with aberrant JNK2 expression.

Keywords: JNK2, WNT, Axin2, proliferation, esophageal squamous cell carcinoma, MAPKK.

« Previous Next »
[1]
Abnet CC, Arnold M, Wei WQ. Epidemiology of esophageal squamous cell carcinoma. Gastroenterology 2018; 154(2): 360-73.
[http://dx.doi.org/10.1053/j.gastro.2017.08.023] [PMID: 28823862]
[2]
Morgan E, Soerjomataram I, Rumgay H, et al. The global landscape of esophageal squamous cell carcinoma and esophageal adenocarcinoma incidence and mortality in 2020 and projections to 2040: New estimates from GLOBOCAN 2020. Gastroenterology 2022; 163(3): 649-658.e2.
[http://dx.doi.org/10.1053/j.gastro.2022.05.054] [PMID: 35671803]
[3]
Qiu L, Yue J, Ding L, Yin Z, Zhang K, Zhang H. Cancer-associated fibroblasts: An emerging target against esophageal squamous cell carcinoma. Cancer Lett 2022; 546: 215860.
[http://dx.doi.org/10.1016/j.canlet.2022.215860] [PMID: 35948121]
[4]
Wang M, Smith JS, Wei WQ. Tissue protein biomarker candidates to predict progression of esophageal squamous cell carcinoma and precancerous lesions. Ann N Y Acad Sci 2018; 1434(1): 59-69.
[http://dx.doi.org/10.1111/nyas.13863] [PMID: 29882970]
[5]
Nakagawa S, Kanda T, Kosugi S, Ohashi M, Suzuki T, Hatakeyama K. Recurrence pattern of squamous cell carcinoma of the thoracic esophagus after extended radical esophagectomy with three-field lymphadenectomy. J Am Coll Surg 2004; 198(2): 205-11.
[http://dx.doi.org/10.1016/j.jamcollsurg.2003.10.005] [PMID: 14759776]
[6]
Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell 2000; 103(2): 239-52.
[http://dx.doi.org/10.1016/S0092-8674(00)00116-1] [PMID: 11057897]
[7]
Wu Q, Wu W, Fu B, Shi L, Wang X, Kuca K. JNK signaling in cancer cell survival. Med Res Rev 2019; 39(6): 2082-104.
[http://dx.doi.org/10.1002/med.21574] [PMID: 30912203]
[8]
Eferl R, Wagner EF. AP-1: A double-edged sword in tumorigenesis. Nat Rev Cancer 2003; 3(11): 859-68.
[http://dx.doi.org/10.1038/nrc1209] [PMID: 14668816]
[9]
Song Y, Li L, Ou Y, et al. Identification of genomic alterations in oesophageal squamous cell cancer. Nature 2014; 509(7498): 91-5.
[http://dx.doi.org/10.1038/nature13176] [PMID: 24670651]
[10]
Ke H, Harris R, Coloff JL, et al. The c-Jun NH2-terminal kinase 2 plays a dominant role in human epidermal neoplasia. Cancer Res 2010; 70(8): 3080-8.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-2923] [PMID: 20354187]
[11]
Zhang JY, Adams AE, Ridky TW, Tao S, Khavari PA. Tumor necrosis factor receptor 1/c-Jun-NH2-kinase signaling promotes human neoplasia. Cancer Res 2007; 67(8): 3827-34.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-4017] [PMID: 17440097]
[12]
Wen J, Hu Y, Liu Q, et al. miR-424 coordinates multilayered regulation of cell cycle progression to promote esophageal squamous cell carcinoma cell proliferation. EBioMedicine 2018; 37: 110-24.
[http://dx.doi.org/10.1016/j.ebiom.2018.10.043] [PMID: 30361064]
[13]
Zeke A, Misheva M, Reményi A, Bogoyevitch MA. JNK signaling: Regulation and functions based on complex protein-protein partnerships. Microbiol Mol Biol Rev 2016; 80(3): 793-835.
[http://dx.doi.org/10.1128/MMBR.00043-14] [PMID: 27466283]
[14]
Lee MH, Padmashali R, Koria P, Andreacas ST. JNK regulates binding of α-catenin to adherens junctions and cell-cell adhesion. FASEB J 2011; 25(2): 613-23.
[http://dx.doi.org/10.1096/fj.10-161380] [PMID: 21030692]
[15]
Lee MH, Koria P, Qu J, Andreadis ST. JNK phosphorylates β-catenin and regulates adherens junctions. FASEB J 2009; 23(11): 3874-83.
[http://dx.doi.org/10.1096/fj.08-117804] [PMID: 19667122]
[16]
Zeke A, Bastys T, Alexa A, et al. Systematic discovery of linear binding motifs targeting an ancient protein interaction surface on MAP kinases. Mol Syst Biol 2015; 11(11): 837.
[http://dx.doi.org/10.15252/msb.20156269] [PMID: 26538579]
[17]
Maruyama T, Mirando AJ, Deng CX, Hsu W. The balance of WNT and FGF signaling influences mesenchymal stem cell fate during skeletal development. Sci Signal 2010; 3(123): ra40.
[http://dx.doi.org/10.1126/scisignal.2000727] [PMID: 20501936]
[18]
Pai SG, Carneiro BA, Mota JM, et al. Wnt/beta-catenin pathway: Modulating anticancer immune response. J Hematol Oncol 2017; 10(1): 101.
[http://dx.doi.org/10.1186/s13045-017-0471-6] [PMID: 28476164]
[19]
Sanson R, Luzzara SL, Cune D, et al. Axin1 protects colon carcinogenesis by an immune-mediated effect. Cell Mol Gastroenterol Hepatol 2023; 15(3): 689-715.
[PMID: 36356835]
[20]
Ngan HL, Law CH, Choi YCY, Chan JYS, Lui VWY. Precision drugging of the MAPK pathway in head and neck cancer. NPJ Genom Med 2022; 7(1): 20.
[http://dx.doi.org/10.1038/s41525-022-00293-1] [PMID: 35296678]
[21]
Pan Y, Liu J, Gao Y, et al. FBXW7 loss of function promotes esophageal squamous cell carcinoma progression via elevating MAP4 and ERK phosphorylation. J Exp Clin Cancer Res 2023; 42(1): 75.
[http://dx.doi.org/10.1186/s13046-023-02630-3] [PMID: 36991467]
[22]
Wang JL, Mu XY, Ma R, Bai XH, Zhao ZJ, Wang YY. Silencing UBQLN2 enhances the radiosensitivity of esophageal squamous cell carcinoma (ESCC) via activating p38 MAPK. J Oncol 2023; 2023: 1-11.
[http://dx.doi.org/10.1155/2023/2339732] [PMID: 36644234]
[23]
Gao YP, Li L, Yan J, et al. Down-regulation of CIDEA promoted tumor growth and contributed to cisplatin resistance by regulating the JNK-p21/Bad signaling pathways in esophageal squamous cell carcinoma. Front Oncol 2021; 10: 627845.
[http://dx.doi.org/10.3389/fonc.2020.627845] [PMID: 33614508]
[24]
Zou S, Yang J, Guo J, et al. RAD18 promotes the migration and invasion of esophageal squamous cell cancer via the JNK-MMPs pathway. Cancer Lett 2018; 417: 65-74.
[http://dx.doi.org/10.1016/j.canlet.2017.12.034] [PMID: 29306013]
[25]
Qin X, Zheng S, Liu T, et al. Roles of phosphorylated JNK in esophageal squamous cell carcinomas of kazakh ethnic. Mol Carcinog 2014; 53(7): 526-36.
[http://dx.doi.org/10.1002/mc.22004] [PMID: 23359384]
[26]
Bogoyevitch MA, Kobe B. Uses for JNK: The many and varied substrates of the c-Jun N-terminal kinases. Microbiol Mol Biol Rev 2006; 70(4): 1061-95.
[http://dx.doi.org/10.1128/MMBR.00025-06] [PMID: 17158707]
[27]
Li AFY, Hsu PK, Tzao C, et al. Reduced axin protein expression is associated with a poor prognosis in patients with squamous cell carcinoma of esophagus. Ann Surg Oncol 2009; 16(9): 2486-93.
[http://dx.doi.org/10.1245/s10434-009-0593-3] [PMID: 19582507]
[28]
Nakajima M, Fukuchi M, Miyazaki T, Masuda N, Kato H, Kuwano H. Reduced expression of Axin correlates with tumour progression of oesophageal squamous cell carcinoma. Br J Cancer 2003; 88(11): 1734-9.
[http://dx.doi.org/10.1038/sj.bjc.6600941] [PMID: 12771989]
[29]
Chong CR, Jänne PA. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med 2013; 19(11): 1389-400.
[http://dx.doi.org/10.1038/nm.3388] [PMID: 24202392]
[30]
Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med 2008; 358(11): 1160-74.
[http://dx.doi.org/10.1056/NEJMra0707704] [PMID: 18337605]
[31]
Massagué J. Transforming growth factor-alpha. A model for membrane-anchored growth factors. J Biol Chem 1990; 265(35): 21393-6.
[http://dx.doi.org/10.1016/S0021-9258(18)45745-6] [PMID: 2254298]
[32]
Shoyab M, McDonald VL, Bradley JG, Todaro GJ. Amphiregulin: A bifunctional growth-modulating glycoprotein produced by the phorbol 12-myristate 13-acetate-treated human breast adenocarcinoma cell line MCF-7. Proc Natl Acad Sci USA 1988; 85(17): 6528-32.
[http://dx.doi.org/10.1073/pnas.85.17.6528] [PMID: 3413110]
[33]
Toyoda H, Komurasaki T, Uchida D, et al. Epiregulin. A novel epidermal growth factor with mitogenic activity for rat primary hepatocytes. J Biol Chem 1995; 270(13): 7495-500.
[PMID: 7706296]
[34]
Strachan L, Murison JG, Prestidge RL, Sleeman MA, Watson JD, Kumble KD. Cloning and biological activity of epigen, a novel member of the epidermal growth factor superfamily. J Biol Chem 2001; 276(21): 18265-71.
[http://dx.doi.org/10.1074/jbc.M006935200] [PMID: 11278323]
[35]
Higashiyama S, Lau K, Besner GE, Abraham JA, Klagsbrun M. Structure of heparin-binding EGF-like growth factor. Multiple forms, primary structure, and glycosylation of the mature protein. J Biol Chem 1992; 267(9): 6205-12.
[http://dx.doi.org/10.1016/S0021-9258(18)42682-8] [PMID: 1556128]
[36]
Sawada G, Niida A, Uchi R, et al. Genomic landscape of esophageal squamous cell carcinoma in a Japanese population. Gastroenterology 2016; 150(5): 1171-82.
[http://dx.doi.org/10.1053/j.gastro.2016.01.035] [PMID: 26873401]
[37]
Yang YM, Hong P, Xu WW, He QY, Li B. Advances in targeted therapy for esophageal cancer. Signal Transduct Target Ther 2020; 5(1): 229.
[http://dx.doi.org/10.1038/s41392-020-00323-3] [PMID: 33028804]
[38]
Freed DM, Bessman NJ, Kiyatkin A, et al. EGFR ligands differentially stabilize receptor dimers to specify signaling kinetics. Cell 2017; 171(3): 683-695.e18.
[http://dx.doi.org/10.1016/j.cell.2017.09.017] [PMID: 28988771]
[39]
Morgan EL, Scarth JA, Patterson MR, et al. E6-mediated activation of JNK drives EGFR signalling to promote proliferation and viral oncoprotein expression in cervical cancer. Cell Death Differ 2021; 28(5): 1669-87.
[http://dx.doi.org/10.1038/s41418-020-00693-9] [PMID: 33303976]
[40]
Koch P, Gehringer M, Laufer SA. Inhibitors of c-Jun N-terminal kinases: An update. J Med Chem 2015; 58(1): 72-95.
[http://dx.doi.org/10.1021/jm501212r] [PMID: 25415535]
[41]
Hunot S, Vila M, Teismann P, et al. JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson’s disease. Proc Natl Acad Sci USA 2004; 101(2): 665-70.
[http://dx.doi.org/10.1073/pnas.0307453101] [PMID: 14704277]
[42]
Assi K, Pillai R, Gómez-Muñoz A, Owen D, Salh B. The specific JNK inhibitor SP600125 targets tumour necrosis factor-alpha production and epithelial cell apoptosis in acute murine colitis. Immunology 2006; 118(1): 112-21.
[http://dx.doi.org/10.1111/j.1365-2567.2006.02349.x] [PMID: 16630028]
[43]
Gross ND, Boyle JO, Du B, et al. Inhibition of Jun NH2-terminal kinases suppresses the growth of experimental head and neck squamous cell carcinoma. Clin Cancer Res 2007; 13(19): 5910-7.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-0352] [PMID: 17908987]
[44]
Carboni S, Hiver A, Szyndralewiez C, Gaillard P, Gotteland JP, Vitte PA. AS601245 (1,3-benzothiazol-2-yl(2-[[2-(3-pyridinyl) ethyl]amino]-4-pyrimidinyl)acetonitrile): A c-Jun NH2-terminal protein kinase inhibitor with neuroprotective properties. J Pharmacol Exp Ther 2004; 310(1): 25-32.
[http://dx.doi.org/10.1124/jpet.103.064246] [PMID: 14988419]
[45]
Messoussi A, Feneyrolles C, Bros A, et al. Recent progress in the design, study, and development of c-Jun N-terminal kinase inhibitors as anticancer agents. Chem Biol 2014; 21(11): 1433-43.
[http://dx.doi.org/10.1016/j.chembiol.2014.09.007] [PMID: 25442375]
[46]
Zhang T, Inesta-Vaquera F, Niepel M, et al. Discovery of potent and selective covalent inhibitors of JNK. Chem Biol 2012; 19(1): 140-54.
[http://dx.doi.org/10.1016/j.chembiol.2011.11.010] [PMID: 22284361]
[47]
Wang W, Shi L, Xie Y, et al. SP600125, a new JNK inhibitor, protects dopaminergic neurons in the MPTP model of Parkinson’s disease. Neurosci Res 2004; 48(2): 195-202.
[http://dx.doi.org/10.1016/j.neures.2003.10.012] [PMID: 14741394]
[48]
Chen N, Nomura M, She QB, et al. Suppression of skin tumorigenesis in c-Jun NH(2)-terminal kinase-2-deficient mice. Cancer Res 2001; 61(10): 3908-12.
[PMID: 11358804]
[49]
Hui L, Zatloukal K, Scheuch H, Stepniak E, Wagner EF. Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation. J Clin Invest 2008; 118(12): 3943-53.
[http://dx.doi.org/10.1172/JCI37156] [PMID: 19033664]
[50]
Lu W, Liu Y, Gao Y, et al. Development of a covalent inhibitor of c-Jun N-terminal protein kinase (JNK) 2/3 with selectivity over JNK1. J Med Chem 2023; 66(5): 3356-71.
[http://dx.doi.org/10.1021/acs.jmedchem.2c01834] [PMID: 36826833]

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