title: TBL1XR1 promotes lymphangiogenesis and lymphatic metastasis in esophageal squamous cell carcinoma.
abstract: OBJECTIVE
  Transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) plays an important role in controlling the precisely regulated switch between gene repression and gene activation in transcriptional regulation. We investigated its biological function and clinical significance in esophageal squamous cell carcinoma (ESCC).
  
  
  METHODS
  Immunoblotting and immunochemistry were used to determine TBL1XR1 expression in ESCC cell lines, ESCC clinical tissues and 230 clinicopathologically characterised ESCC specimens. The role of TBL1XR1 in lymphangiogenesis and lymphatic metastasis was examined by tube formation, cell invasion and wound-healing assays in vitro, and by a popliteal lymph node metastasis model in vivo. The molecular mechanism by which TBL1XR1 upregulates vascular endothelial growth factor C (VEGF-C) expression was explored using real-time PCR, ELISA, luciferase reporter assay and chromatin immunoprecipitation.
  
  
  RESULTS
  TBL1XR1 expression was significantly upregulated in ESCC, positively correlated with disease stage and patient survival, and identified as an independent prognostic factor for patient outcome. We found that TBL1XR1 overexpression promoted lymphangiogenesis and lymphatic metastasis in ESCC in vitro and in vivo, whereas TBL1XR1 silencing had the converse effect. We demonstrated that TBL1XR1 induced VEGF-C expression by binding to the VEGF-C promoter. We confirmed the correlation between TBL1XR1 and VEGF-C expression in a large cohort of clinical ESCC samples and through analysis of published datasets in gastric, colorectal and breast cancer.
  
  
  CONCLUSIONS
  Our results demonstrated that TBL1XR1 induced lymphangiogenesis and lymphatic metastasis in ESCC via upregulation of VEGF-C, and may represent a novel prognostic biomarker and therapeutic target for patients with ESCC.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China Department of Cardiothoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China Guangzhou Research Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease, Guangzhou, Guangdong, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Chuyong
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Weijiang
authors.initials: W
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Aibin
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Jueheng
authors.initials: J
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Pengli
authors.initials: P
authors.lastname: Ren
authors.affiliation: Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Libing
authors.initials: L
authors.lastname: Song
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000556:secondary*; D004938:Esophageal Neoplasms / Q000556:secondary*; D000077277:Esophageal Squamous Cell Carcinoma; D006801:Humans; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D009687:Nuclear Proteins / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D014407:Tumor Cells, Cultured; D042582:Vascular Endothelial Growth Factor C / Q000502:physiology
chemical_list: D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C473691:TBL1XR1 protein, human; D042582:Vascular Endothelial Growth Factor C