title: Novel roles of c-Met in the survival of renal cancer cells through the regulation of HO-1 and PD-L1 expression.
abstract: The receptor tyrosine kinase c-Met is overexpressed in renal cancer cells and can play major role in the growth and survival of tumor. We investigated how the c-Met-mediated signaling through binding to its ligand hepatocyte growth factor (HGF) can modulate the apoptosis and immune escape mechanism(s) of renal cancer cells by the regulations of novel molecules heme oxygenase-1 (HO-1) and programmed death-1 ligand 1 (PD-L1). We found that HGF/c-Met-mediated signaling activated the Ras/Raf pathway and down-regulated cancer cell apoptosis; and it was associated with the overexpression of cytoprotective HO-1 and anti-apoptotic Bcl-2/Bcl-xL. c-Met-induced HO-1 overexpression was regulated at the transcriptional level. Next, we observed that c-Met induction markedly up-regulated the expression of the negative co-stimulatory molecule PD-L1, and this can be prevented following treatment of the cells with pharmacological inhibitors of c-Met. Interestingly, HGF/c-Met-mediated signaling could not induce PD-L1 at the optimum level when either Ras or HO-1 was knocked down. To study the functional significance of c-Met-induced PD-L1 expression, we performed a co-culture assay using mouse splenocytes (expressing PD-L1 receptor PD-1) and murine renal cancer cells (RENCA, expressing high PD-L1). We observed that the splenocyte-mediated apoptosis of cancer cells during co-culture was markedly increased in the presence of either c-Met inhibitor or PD-L1 neutralizing antibody. Finally, we found that both c-Met and PD-L1 are significantly up-regulated and co-localized in human renal cancer tissues. Together, our study suggests a novel mechanism(s) by which c-Met can promote increased survival of renal cancer cells through the regulation of HO-1 and PD-L1.
authors: From the Division of Nephrology, Boston Children's Hospital, Harvard Medical School, and.
authors: Murugabaskar
authors: M
authors: Balan
authors: From the Division of Nephrology, Boston Children's Hospital.
authors: Eduardo
authors: E
authors: Mier y Teran
authors: Department of Surgery, Molecular Oncology, and Immunology, University of Wurzburg, 97080 Wurzburg, Germany.
authors: Ana Maria
authors: AM
authors: Waaga-Gasser
authors: Department of Surgery, Molecular Oncology, and Immunology, University of Wurzburg, 97080 Wurzburg, Germany.
authors: Martin
authors: M
authors: Gasser
authors: Harvard Medical School, and Dana Farber Cancer Institute, Boston, Massachusetts 02115 and.
authors: Toni K
authors: TK
authors: Choueiri
authors: Harvard Medical School, and Dana Farber Cancer Institute, Boston, Massachusetts 02115 and.
authors: Gordon
authors: G
authors: Freeman
authors: From the Division of Nephrology, Boston Children's Hospital, Harvard Medical School, and soumitro.pal@childrens.harvard.edu.
authors: Soumitro
authors: S
authors: Pal
mesh_terms: D000818:Animals; D017209:Apoptosis; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D002470:Cell Survival; D018920:Coculture Techniques; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D008807:Mice, Inbred BALB C; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D019139:Tumor Escape; D018631:ras Proteins / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D018631:ras Proteins
keywords: PD-L1; Ras protein; apoptosis; c-Met; cancer; heme oxygenase; hepatocyte growth factor/scatter factor (HGF/SF); renal cancer; signal transduction
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