title: Regulation of Oral Squamous Cell Carcinoma Proliferation Through Crosstalk Between SMAD7 and CYLD.
abstract: OBJECTIVE
  SMAD7 is a key inhibitor of transforming growth factor β (TGFβ) receptor signaling, which regulates the alteration of cancer cell invasiveness through epithelial-mesenchymal cell conversion. Dysfunction of protein ubiquitination plays a critical role in carcinogenesis, whereas the involvement a deubiquitinating enzyme, cylindromatosis gene (CYLD), in the tumor invasion of oral squamous cell carcinoma (OSCC) is unknown.
  
  
  METHODS
  Here, we studied the role of CYLD in regulation of OSCC cell invasion, using clinic specimens and cell lines. We modified SMAD7 levels in OSCC cells, and examined its effects on CYLD mRNA and protein levels by RT-qPCR and by Western blot, respectively. We also modified CYLD levels in OSCC cells, and examined its effects on SMAD7 mRNA and protein levels by RT-qPCR and by Western blot, respectively. Then, we examined the cell invasiveness in CYLD and/or SMAD7-modified OSCC cells in a transwell cell invasion assay.
  
  
  RESULTS
  We found that the levels of CYLD and SMAD7 were significantly decreased in OSCC specimens, compared to the paired normal tissue. Metastatic OSCC appeared to contained lower levels of CYLD and SMAD7. Moreover, CYLD and SMAD7 levels strongly correlated in OSCC specimens. Low CYLD levels were associated with poor patients' survival. Moreover, SMAD did not regulate CYLD, but CYLD regulated the levels of SMAD7 in OSCC cells. Furthermore, CYLD overexpression inhibited SMAD7-mediated cell invasion, while CYLD depletion increased SMAD7-mediated cell invasion in OSCC cells.
  
  
  CONCLUSIONS
  Suppression of CYLD in OSCC cells may promote SMAD7-mediated cancer invasion. Thus, CYLD appears to be an intriguing therapeutic target to prevent OSCC metastases.
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Ge
authors.forename: Jun-Feng
authors.initials: JF
authors.lastname: Xu
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D000074749:Deubiquitinating Enzyme CYLD; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011379:Prognosis; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics* / Q000378:metabolism*; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C497806:SMAD7 protein, human; D051906:Smad7 Protein; D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD