Mitogen-inducible gene 6 (MIG6) holds a special position in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance. As MIG6 regulates the activity of EGFR signal pathway negatively, high level of MIG6 can increase the EGFR TKI resistance of cancer cells, and limit the therapeutic action of EGFR TKI, such as gefitinib or erlotinib. Therefore, better understanding of the molecular mechanisms underlying the regulation of EGFR TKI resistance holds great value in cancer therapy.
Methods:
In our study, we mainly explored the function of transcription activator, myocyte enhancer factor 2C (MEF2C), on MIG6 expression as well as gefitinib-resistant ability of hepatic cancer cells.
Results:
Our results indicated that both MEF2C and MIG6 could be upregulated in gefitinib-resistant cancer tissues and cancer cell lines compared with gefitinib-sensitive ones. Chromatin immunoprecipitation assay and dual luciferase assay showed that MEF2C could bind to the MEF2C element in the promoter sequence of MIG6 and promote the transcription of MIG6. This effect increased the gefitinib-resistant ability of cancer cells. Therefore, MEF2C knockdown inhibited the gefitinib resistance and limited the proliferation of hepatic cancer cells in vitro and in vivo, while overexpression of MEF2C showed opposite effect on cancer cell proliferation.
Conclusion:
Our study provides novel insight into the regulation mechanism of MIG6 and suggests potential implications for the therapeutic strategies of gefitinib resistance through inhibiting MEF2C in hepatic cancer cells.
ReschkeMFerbyIStepniakEet al. Mitogen-inducible gene-6 is a negative regulator of epidermal growth factor receptor signaling in hepatocytes and human hepatocellular carcinoma. Hepatology2010; 51: 1383–1390.
4.
AnastasiSSalaGHuipingCet al. Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to herceptin. Oncogene2005; 24: 4540–4548.
5.
LinCIDuJShenWTet al. Mitogen-inducible gene-6 is a multifunctional adaptor protein with tumor suppressor-like activity in papillary thyroid cancer. J Clin Endocrinol Metab2011; 96: E554–565.
6.
BallaroCCeccarelliSTiveronCet al. Targeted expression of RALT in mouse skin inhibits epidermal growth factor receptor signalling and generates a Waved-like phenotype. EMBO Rep2005; 6: 755–761.
7.
FerbyIReschkeMKudlacekOet al. Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis and tumor formation. Nat Med2006; 12: 568–573.
8.
KimTHLeeDKChoSNet al. Critical tumor suppressor function mediated by epithelial Mig-6 in endometrial cancer. Cancer Res2013; 73: 5090–5099.
KimTHYooJYKimHIet al. Mig-6 suppresses endometrial cancer associated with Pten deficiency and ERK activation. Cancer Res2014; 74: 7371–7382.
11.
ZhangYWVande WoudeGF.Mig-6, signal transduction, stress response and cancer. Cell Cycle2007; 6: 507–513.
12.
MaSFGrigoryevDNTaylorADet al. Bioinformatic identification of novel early stress response genes in rodent models of lung injury. Am J Physiol Lung Cell Mol Physiol2005; 289: L468–477.
13.
XuDPattenRDForceTet al. Gene 33/RALT is induced by hypoxia in cardiomyocytes, where it promotes cell death by suppressing phosphatidylinositol 3-kinase and extracellular signal-regulated kinase survival signaling. Mol Cell Biol2006; 26: 5043–5054.
14.
ZhangYWSuYLanningNet al. Targeted disruption of Mig-6 in the mouse genome leads to early onset degenerative joint disease. Proc Natl Acad Sci USA2005; 102: 11740–11745.
15.
ChangXIzumchenkoESolisLMet al. The relative expression of Mig6 and EGFR is associated with resistance to EGFR kinase inhibitors. PLoS One2013; 8: e68966.
16.
IzumchenkoEChangXFMichailidiCet al. The TGF beta-miR200-MIG6 pathway orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors. Cancer Res2014; 74: 3995–4005.
17.
BlackBLOlsonEN.Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu Rev Cell Dev Biol1998; 14: 167–196.
18.
LinQSchwarzJBucanaCet al. Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science1997; 276: 1404–1407.
19.
Cante-BarrettKPietersRMeijerinkJP.Myocyte enhancer factor 2C in hematopoiesis and leukemia. Oncogene2014; 33: 403–410.
20.
ZhangMZhuBDavieJ.Alternative splicing of MEF2C pre-mRNA controls its activity in normal myogenesis and promotes tumorigenicity in rhabdomyosarcoma cells. J Biol Chem2015; 290: 310–324.
21.
LaszloGSAlonzoTAGudgeonCJet al. High expression of myocyte enhancer factor 2C (MEF2C) is associated with adverse-risk features and poor outcome in pediatric acute myeloid leukemia: a report from the Children’s Oncology Group. J Hematol Oncol2015; 8: 115.
22.
Kawashima-GotoSImamuraTTomoyasuCet al. BCL2 inhibitor (ABT-737): a restorer of prednisolone sensitivity in early T-cell precursor-acute lymphoblastic leukemia with high MEF2C expression?PLoS One2015; 10: e0132926.
23.
ZhangJJZhuYXieKLet al. Yin Yang-1 suppresses invasion and metastasis of pancreatic ductal adenocarcinoma by downregulating MMP10 in a MUC4/ErbB2/p38/MEF2C-dependent mechanism. Mol Cancer2014; 13: 130.
24.
LiuPFengYDongDet al. Enhanced renoprotective effect of IGF-1 modified human umbilical cord-derived mesenchymal stem cells on gentamicin-induced acute kidney injury. Sci Rep2016; 6: 20287.
25.
LiuPFengYDongDet al. Enhanced renoprotective efect of IGF-1 modifed human umbilical cord-derived mesenchymal stem cells on gentamicin-induced acute kidney injury. Sci Rep2016; 6: 20287.
26.
LiuPCaiJDongDet al. Effects of SOX2 on proliferation, migration and adhesion of human dental pulp stem cells. PLoS One2015; 10: e0141346.
27.
TaoSLiuPLuoGet al. p97 Negatively regulates NRF2 by extracting ubiquitylated NRF2 from the KEAP1-CUL3 E3 complex. Mol Cell Biol Epub 2017 Jan 17.
28.
BaoLWuJDodsonMet al. ABCF2, an Nrf2 target gene, contributes to cisplatin resistance in ovarian cancer cells. Mol Carcinog2017; 56: 1543–1553.
29.
LiuPFengYDongCet al. Study on therapeutic action of bone marrow derived mesenchymal stem cell combined with vitamin E against acute kidney injury in rats. Life Sci2013; 92: 829–837.
30.
ZhaoLFengYChenXet al. Effects of IGF-1 on neural differentiation of human umbilical cord derived mesenchymal stem cells. Life Sci2016; 151: 93–101.
31.
TsaoMSSakuradaACutzJCet al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med2005; 353: 133–144.
32.
LynchTJBellDWSordellaRet al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med2004; 350: 2129–2139.
33.
PaezJGJannePALeeJCet al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science2004; 304: 1497–1500.
34.
PaoWMillerVAPolitiKAet al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med2005; 2: e73.
35.
PaoWWangTYRielyGJet al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med2005; 2: e17.
36.
EngelmanJAMukoharaTZejnullahuKet al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest2006; 116: 2695–2706.
37.
van den BentMJBrandesAARamplingRet al. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol2009; 27: 1268–1274.
38.
MullerCBDe BastianiMABeckerMet al. Potential crosstalk between cofilin-1 and EGFR pathways in cisplatin resistance of non-small-cell lung cancer. Oncotarget2015; 6: 3531–3539.
39.
Lemos-GonzalezYPaez de la CadenaMRodriguez-BerrocalFJet al. Absence of activating mutations in the EGFR kinase domain in Spanish head and neck cancer patients. Tumour Biol2007; 28: 273–279.
40.
BakkeJWrightWCZamoraAEet al. Transcription factor ZNF148 is a negative regulator of human muscle differentiation. Sci Rep2017; 7: 8138.
41.
DongCYangXZZhangCYet al. Myocyte enhancer factor 2C and its directly-interacting proteins: A review. Prog Biophys Mol Biol2017; 126: 22–30.
42.
GuXFuCLinLet al. miR-124 and miR-9 mediated downregulation of HDAC5 promotes neurite development through activating MEF2C-GPM6A pathway. J Cell Physiol2018; 233: 673–687.
43.
DavilaJLGoffLARicuperoCLet al. A positive feedback mechanism that regulates expression of miR-9 during neurogenesis. Plos One2014; 9: e94348.
44.
Colomer-LahigueraSPiseckerMKonigMet al. MEF2C-dysregulated pediatric T-cell acute lymphoblastic leukemia is associated with CDKN1B deletions and a poor response to glucocorticoid therapy. Leuk Lymphoma2017; 58: 2895–2904.
45.
WangLLiJZhaoHet al. Identifying the crosstalk of dysfunctional pathways mediated by lncRNAs in breast cancer subtypes. Mol Biosyst2016; 12: 711–720.
46.
PilatiCLetouzeENaultJCet al. Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation. Cancer Cell2014; 25: 428–441.
47.
SchulzeKImbeaudSLetouzeEet al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet2015; 47: 505–511.
48.
AhnSMJangSJShimJHet al. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology2014; 60: 1972–1982.
49.
ParraHSCavinaRLatteriFet al. Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib (‘Iressa’, ZD1839) in non-small-cell lung cancer. Br J Cancer2004; 91: 208–212.
50.
CappuzzoFHirschFRRossiEet al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst2005; 97: 643–655.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
