title: c-FLIP is involved in tumor progression of peripheral T-cell lymphoma and targeted by histone deacetylase inhibitors.
abstract: BACKGROUND
  Peripheral T-cell lymphomas (PTCLs) are often aggressive tumors and resistant to conventional chemotherapy. Dysregulation of extrinsic apoptosis plays an important role on tumor cell sensitivity to chemotherapeutic agents. Cellular FLICE inhibitory protein (c-FLIP) is a key regulator of extrinsic apoptotic pathway.
  
  
  METHODS
  c-FLIP expression was assessed by real-time PCR and compared according to clinical parameters in patients with PTCLs. The relation of c-FLIP to tumor cell apoptosis mediated by histone deacetylases inhibitors (HDACIs) and the possible mechanism were examined in T-lymphoma cell lines and in a murine xenograft model.
  
  
  RESULTS
  c-FLIP was overexpressed and associated with decreased tumor TRAIL/DR5 expression, elevated serum lactate dehydrogenase level and high-risk International Prognostic Index of the patients. In vitro, molecular silencing of c-FLIP by specific small-interfering RNA increased TRAIL/DR5 expression, enhanced T-lymphoma cell apoptosis and sensitized cells to chemotherapeutic agents. However, HDACIs valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) could downregulate c-FLIP expression and triggered extrinsic apoptosis of T-lymphoma cells, through inhibiting NF-κB signaling and interrupting P50 interaction with c-FLIP promoter. As Class I HDACIs, both VPA and SAHA inhibited HDAC1, resulting in P50 inactivation and c-FLIP downregulation. In vivo, oral VPA treatment significantly retarded tumor growth and induced in situ apoptosis, consistent with inhibition of HDAC1/P50/c-FLIP axis and increase of TRAIL/DR5 expression.
  
  
  CONCLUSIONS
  c-FLIP overexpression in PTCLs protected tumor cells from extrinsic apoptosis and contributed to tumor progression. Although linking to chemoresistance, c-FLIP indicated tumor cell sensitivity to HDACIs, providing a potential biomarker of targeting apoptosis in treating PTCLs.
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China. zheng_zhong89@163.com.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China. orenge@medmail.com.cn.
authors.forename: Shu
authors.initials: S
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China. wuwen@medmail.com.cn.
authors.forename: Wen
authors.initials: W
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China. wl_wangdong@126.com.|Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China. wl_wangdong@126.com.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China. joyce19890611@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China. shen_yang@126.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China. anne_janin@yahoo.com.|U1165 Inserm/Université Paris 7, Hôpital Saint Louis, Pairs, France. anne_janin@yahoo.com.
authors.forename: Anne
authors.initials: A
authors.lastname: Janin
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China. zhao.weili@yahoo.com.|Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China. zhao.weili@yahoo.com.
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Zhao
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D018450:Disease Progression; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D016411:Lymphoma, T-Cell, Peripheral / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D015398:Signal Transduction
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D056572:Histone Deacetylase Inhibitors