title: Ectopic expression of human MutS homologue 2 on renal carcinoma cells is induced by oxidative stress with interleukin-18 promotion via p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) signaling pathways.
abstract: Human MutS homologue 2 (hMSH2), a crucial element of the highly conserved DNA mismatch repair system, maintains genetic stability in the nucleus of normal cells. Our previous studies indicate that hMSH2 is ectopically expressed on the surface of epithelial tumor cells and recognized by both T cell receptor γδ (TCRγδ) and natural killer group 2 member D (NKG2D) on Vδ2 T cells. Ectopically expressed hMSH2 could trigger a γδ T cell-mediated cytolysis. In this study, we showed that oxidative stress induced ectopic expression of hMSH2 on human renal carcinoma cells. Under oxidative stress, both p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) pathways have been confirmed to mediate the ectopic expression of hMSH2 through the apoptosis-signaling kinase 1 (ASK1) upstream and activating transcription factor 3 (ATF3) downstream of both pathways. Moreover, renal carcinoma cell-derived interleukin (IL)-18 in oxidative stress was a prominent stimulator for ectopically induced expression of hMSH2, which was promoted by interferon (IFN)-γ as well. Finally, oxidative stress or pretreatment with IL-18 and IFN-γ enhanced γδ T cell-mediated cytolysis of renal carcinoma cells. Our results not only establish a mechanism of ectopic hMSH2 expression in tumor cells but also find a biological linkage between ectopic expression of hMSH2 and activation of γδ T cells in stressful conditions. Because γδ T cells play an important role in the early stage of innate anti-tumor response, γδ T cell activation triggered by ectopically expressed hMSH2 may be an important event in immunosurveillance for carcinogenesis.
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Peking Union Medical College, Beijing 100005, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Mo
authors.forename: Yumei
authors.initials: Y
authors.lastname: Dai
authors.forename: Ning
authors.initials: N
authors.lastname: Kang
authors.forename: Lianxian
authors.initials: L
authors.lastname: Cui
authors.forename: Wei
authors.initials: W
authors.lastname: He
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019169:Jurkat Cells; D020014:K562 Cells; D007680:Kidney Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051718:MutS Homolog 2 Protein / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D018384:Oxidative Stress; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D020382:Interleukin-18; D016692:Receptors, Antigen, T-Cell, gamma-delta; D007371:Interferon-gamma; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein