Volume 5 Issue 2
Dec.  2021
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Qiuyan Xia, Jiajia Jiang, Wei Zhao, Qi Tang, Xiaohua Li, Tengqi Wang, Yan Zhou. Epiregulin promotes growth and metastasis of gastric cancer via the ERK/JNK/p38 signaling pathway[J]. Blood&Genomics, 2021, 5(2): 135-145. doi: 10.46701/BG.2021022021125
Citation: Qiuyan Xia, Jiajia Jiang, Wei Zhao, Qi Tang, Xiaohua Li, Tengqi Wang, Yan Zhou. Epiregulin promotes growth and metastasis of gastric cancer via the ERK/JNK/p38 signaling pathway[J]. Blood&Genomics, 2021, 5(2): 135-145. doi: 10.46701/BG.2021022021125

Epiregulin promotes growth and metastasis of gastric cancer via the ERK/JNK/p38 signaling pathway

doi: 10.46701/BG.2021022021125
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  • Corresponding author: Tengqi Wang, Cancer Center, Bayannur Hospital, Bayannur, Inner Mongolia 015000, China. E-mail: 3571194211@qq.com; Yan Zhou, Department of Oncology, the Affiliated Aoyang Hospital of Jiangsu University, Zhangjiagang, Jiangsu 215617, China. E-mail: yanzhou@yeah.net
  • Received Date: 2021-08-08
  • Accepted Date: 2021-11-29
  • Rev Recd Date: 2021-11-24
  • Available Online: 2022-01-06
  • Publish Date: 2021-12-31
  • Epiregulin (EREG) is a ligand of the epidermal growth factor receptor. It belongs to the ErbB family of ligands found overexpressed in various cancers such as colon cancer and lung carcinoma and is likely to play diverse oncogenic roles in several other cancer types. However, little is known about the mechanisms of EREG in the pathogenesis of gastric cancer (GC). The present study was undertaken to investigate whether EREG influences the development and progression in GC. The results revealed that EREG was found to be overexpressed in human GC cells lines. Moreover, EREG induced cell migration, invasion, and proliferation, and inhibited apoptosis in vitro. The study also found that EREG depletion inhibited tumor growth in vivo. Our findings indicated that EREG activated the ERK/JNK/p38 signaling pathway and PI3K/Akt signaling pathways to promote GC malignant progression. Overall, this study suggests that EREG may promote GC development and progression through the ERK/JNK/p38 and PI3K/Akt signaling pathways, which may improve our understanding of the molecular mechanism of EREG in GC. Thus, EREG may be a potential target for GC treatment.

     

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  • [1]
    Smyth EC, Nilsson M, Grabsch HI, et al. Gastric cancer[J]. Lancet, 2020, 396(10251): 635−648. doi: 10.1016/S0140-6736(20)31288-5
    [2]
    Zong L, Abe M, Seto Y, et al. The challenge of screening for early gastric cancer in China[J]. Lancet, 2016, 388(10060): 2606. doi: 10.1016/S0140-6736(16)32226-7
    [3]
    Das M. Neoadjuvant chemotherapy: survival benefit in gastric cancer[J]. Lancet Oncol, 2017, 18(6): e307. doi: 10.1016/S1470-2045(17)30321-2
    [4]
    Ilson DH. Targeting the vascular endothelial growth factor pathway in gastric cancer: a hit or a miss?[J]. J Clin Oncol, 2016, 34(13): 1431−1432. doi: 10.1200/JCO.2015.65.8666
    [5]
    Burki TK. Progression-free survival with regorafenib in gastric cancer[J]. Lancet Oncol, 2016, 17(8): e323. doi: 10.1016/S1470-2045(16)30284-4
    [6]
    Aoyama T, Nishikawa K, Fujitani K, et al. Early results of a randomized two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of cisplatin/S-1 and docetaxel/cisplatin/S-1 as neoadjuvant chemotherapy for locally advanced gastric cancer[J]. Ann Oncol, 2017, 28(8): 1876−1881. doi: 10.1093/annonc/mdx236
    [7]
    Alsina M, Gullo I, Carneiro F. Intratumoral heterogeneity in gastric cancer: a new challenge to face[J]. Ann Oncol, 2017, 28(5): 912−913. doi: 10.1093/annonc/mdx134
    [8]
    Röcken C. Molecular classification of gastric cancer[J]. Expert Rev Mol Diagn, 2017, 17(3): 293−301. doi: 10.1080/14737159.2017.1286985
    [9]
    Amon. Antibody improves survival in gastric cancer[J]. Cancer Discovery, 2016, 6(8): OF8. doi: 10.1158/2159-8290.CD-NB2016-077
    [10]
    Martin LJ, Smith SB, Khoutorsky A, et al. Epiregulin and EGFR interactions are involved in pain processing[J]. J Clin Invest, 2017, 127(9): 3353−3366. doi: 10.1172/JCI87406
    [11]
    Pradhan SA, Rather MI, Tiwari A, et al. Evidence that TSC2 acts as a transcription factor and binds to and represses the promoter of Epiregulin[J]. Nucleic Acids Res, 2014, 42(10): 6243−6255. doi: 10.1093/nar/gku278
    [12]
    Xu X, Chen W, Leng S, et al. Muc1 knockout potentiates murine lung carcinogenesis involving an epiregulin-mediated EGFR activation feedback loop[J]. Carcinogenesis, 2017, 38(6): 604−614. doi: 10.1093/carcin/bgx039
    [13]
    Kohsaka S, Hinohara K, Wang L, et al. Epiregulin enhances tumorigenicity by activating the ERK/MAPK pathway in glioblastoma[J]. Neuro Oncol, 2014, 16(7): 960−970. doi: 10.1093/neuonc/not315
    [14]
    Rizzi M, Pittarella P, Sabbatini M, et al. Epiregulin induces human SK-N-BE cell differentiation through ERK1/2 signaling pathway[J]. Growth Factors, 2013, 31(3): 90−97. doi: 10.3109/08977194.2013.795958
    [15]
    Neufert C, Becker C, Türeci Ö, et al. Tumor fibroblast-derived epiregulin promotes growth of colitis-associated neoplasms through ERK[J]. J Clin Invest, 2013, 123(4): 1428−1443. doi: 10.1172/JCI63748
    [16]
    Cao Y, Xia DS, Qi SR, et al. Epiregulin can promote proliferation of stem cells from the dental apical papilla via MEK/Erk and JNK signalling pathways[J]. Cell Prolif, 2013, 46(4): 447−456. doi: 10.1111/cpr.12039
    [17]
    Llovet P, Sastre J, Ortega JS, et al. Prognostic value of BRAF, PI3K, PTEN, EGFR copy number, amphiregulin and epiregulin status in patients with KRAS codon 12 wild-type metastatic colorectal cancer receiving first-line chemotherapy with anti-EGFR therapy[J]. Mol Diagn Ther, 2015, 19(6): 397−408. doi: 10.1007/s40291-015-0165-0
    [18]
    Takahashi N, Yamada Y, Furuta K, et al. Serum levels of hepatocyte growth factor and epiregulin are associated with the prognosis on anti-EGFR antibody treatment in KRAS wild-type metastatic colorectal cancer[J]. Br J Cancer, 2014, 110(11): 2716−2727. doi: 10.1038/bjc.2014.230
    [19]
    Fan J bo, Liu W, Zhu X hui, et al. EGFR-AKT-mTOR activation mediates epiregulin-induced pleiotropic functions in cultured osteoblasts[J]. Mol Cell Biochem, 2015, 398(1–2): 105−113. doi: 10.1007/s11010-014-2210-4
    [20]
    Zhao W, Jia L, kuai X, et al. The role and molecular mechanism of Trop2 induced epithelial-mesenchymal transition through mediated β-catenin in gastric cancer[J]. Cancer Med, 2019, 8(3): 1135−1147. doi: 10.1002/cam4.1934
    [21]
    F W, HQ Y, BS H, et al. Upregulated lncRNA-UCA1 contributes to progression of hepatocellular carcinoma through inhibition of miR-216b and activation of FGFR1/ERK signaling pathway[J]. Oncotarget, 2015, 6(10): 7899−7917. doi: 10.18632/oncotarget.3219
    [22]
    Seligmann JF, Elliott F, Richman SD, et al. Combined epiregulin and amphiregulin expression levels as a predictive biomarker for panitumumab therapy benefit or lack of benefit in patients with RAS wild-type[J]. JAMA Oncol, 2016, 2(5): 633−642. doi: 10.1001/jamaoncol.2015.6065
    [23]
    Jacobs B, De Roock W, Piessevaux H, et al. Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab[J]. J Clin Oncol, 2009, 27(30): 5068−5074. doi: 10.1200/JCO.2008.21.3744
    [24]
    Takahashi M, Hayashi K, Yoshida K, et al. Epiregulin as a major autocrine/paracrine factor released from ERK- and p38MAPK-activated vascular smooth muscle cells[J]. Circulation, 2003, 108(20): 2524−2529. doi: 10.1161/01.CIR.0000096482.02567.8C
    [25]
    Homma T, Kato A, Sakashita M, et al. Potential involvement of the epidermal growth factor receptor ligand epiregulin and matrix metalloproteinase-1 in pathogenesis of chronic rhinosinusitis[J]. Am J Respir Cell Mol Biol, 2017, 57(3): 334−345. doi: 10.1165/rcmb.2016-0325OC
    [26]
    Q Xia, Y Zhou, H Y, et al. Elevated epiregulin expression predicts poor prognosis in gastric cancer[J]. Pathol Res Pract, 2019, 215(5): 873−879. doi: 10.1016/j.prp.2019.01.030
    [27]
    Ornskov D, Nexo E, Sorensen BS. Insulin induces a transcriptional activation of epiregulin, HB-EGF and amphiregulin, by a PI3K-dependent mechanism: Identification of a specific insulin-responsive promoter element[J]. Biochem Biophys Res Commun, 2007, 354(4): 885−891. doi: 10.1016/j.bbrc.2007.01.047
    [28]
    Zhuang S, Yan Y, Daubert RA, et al. Epiregulin promotes proliferation and migration of renal proximal tubular cells[J]. Am J Physiol Ren Physiol, 2007, 293(1): F219−226. doi: 10.1152/ajprenal.00082.2007
    [29]
    Hu K, Li S lin, Gan Y hua, et al. Epiregulin promotes migration and invasion of salivary adenoid cystic carcinoma cell line SACC-83 through activation of ERK and Akt[J]. Oral Oncol, 2009, 45(2): 156−163. doi: 10.1016/j.oraloncology.2008.04.009
    [30]
    Tripathi SC, Fahrmann JF, Celiktas M, et al. MCAM mediates chemoresistance in small-cell lung cancer via the PI3K/AKT/SOX2 signaling pathway[J]. Cancer Res, 2017, 77(16): 4414−4425. doi: 10.1158/0008-5472.CAN-16-2874
    [31]
    Riese DJ, Cullum RL. Epiregulin: roles in normal physiology and cancer[J]. Semin Cell Dev Biol, 2014, 28: 49−56. doi: 10.1016/j.semcdb.2014.03.005
    [32]
    Farooqui M, Bohrer LR, Brady NJ, et al. Epiregulin contributes to breast tumorigenesis through regulating matrix metalloproteinase 1 and promoting cell survival[J]. Mol Cancer, 2015, 14(1): 138. doi: 10.1186/s12943-015-0408-z
    [33]
    Boyles JS, Atwell S, Druzina Z, et al. Structural basis of selectivity and neutralizing activity of a TGFα/epiregulin specific antibody[J]. Protein Sci, 2016, 25(11): 2028−2036. doi: 10.1002/pro.3023
    [34]
    Iijima M, Anai M, Kodama T, et al. Epiregulin-blocking antibody inhibits epiregulin-dependent EGFR signaling[J]. Biochem Biophys Res Commun, 2017, 489(1): 83−88. doi: 10.1016/j.bbrc.2017.03.006
    [35]
    Belda BJ, Thompson JT, Sinha R, et al. The dietary fatty acid 10E12Z-CLA induces epiregulin expression through COX-2 dependent PGF2α synthesis in adipocytes[J]. Prostaglandins Other Lipid Mediat, 2012, 99(1–2): 30−37. doi: 10.1016/j.prostaglandins.2012.05.001
    [36]
    Liu S, Ye D, Xu D, et al. Autocrine epiregulin activates EGFR pathway for lung metastasis via EMT in salivary adenoid cystic carcinoma[J]. Oncotarget, 2016, 7(18): 25251−25263. doi: 10.18632/oncotarget.7940
    [37]
    Cho MC, Choi HS, Lee S, et al. Epiregulin expression by Ets-1 and ERK signaling pathway in Ki-ras-transformed cells[J]. Biochem Biophys Res Commun, 2008, 377(3): 832−837. doi: 10.1016/j.bbrc.2008.10.053
    [38]
    Singh B, Bogatcheva G, Washington MK, et al. Transformation of polarized epithelial cells by apical mistrafficking of epiregulin[J]. Proc Natl Acad Sci U S A, 2013, 110(22): 8960−8965. doi: 10.1073/pnas.1305508110
    [39]
    Khambata-Ford S, Garrett CR, Meropol NJ, et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab[J]. J Clin Oncol, 2007, 25(22): 3230−3237. doi: 10.1200/JCO.2006.10.5437
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