title: Up-regulation of HB-EGF by the COX-2/PGE2 signaling associates with the cisplatin resistance and tumor recurrence of advanced HNSCC.
abstract: OBJECTIVE
  When treating advanced HNSCC, a cisplatin-based systemic regimen benefit patient survival. However, chemoresistance will greatly reduce the effectiveness of this approach. The identification of molecules that contribute to cisplatin resistance may potentially improve the survival. Both HB-EGF and COX-2 have been reported to increase cisplatin-resistance. Here, we have focused on the regulation of HB-EGF/COX-2 and their roles in cisplatin resistance.
  
  
  METHODS
  IHC staining was used to measure the expression levels of HB-EGF and COX-2 on the tissue microarray from 43 tissue samples of patients with advanced HNSCC. siRNA, western blot and qRT-PCR were used to dissect the regulation between EGF, Akt, COX-2, PGE2, and cisplatin sensitivity. The correlation between HB-EGF, COX2 and HNSCC progression was analyzed by the receiver operating characteristic (ROC) curve and Kaplan-Meier disease free survival.
  
  
  RESULTS
  Patients of advanced HNSCC patients with increased HB-EGF and COX-2 expression have higher tumor recurrent rates that was related to cisplatin resistance. The resistance was mediated via an increased expression of HB-EGF and COX-2. The activation of Akt by either EGF or areca nut extract were able to upregulate COX-2, which would increase the expression of HB-EGF in a PGE2 dependent manner. Inhibition and knockdown of COX-2 resulted in a decrease in HB-EGF. In the tissue samples from HNSCC patients, there was a significant positive correlation between the expression of COX-2 and HB-EGF.
  
  
  CONCLUSIONS
  Our results suggested that COX-2 and HB-EGF are important in development of HNSCC cisplatin resistance. These findings may help the development of new strategies for overcoming cisplatin resistance.
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan; School of Dentistry, National Yang-Ming University, Taipei, Taiwan; Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Yang
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan; School of Dentistry, National Yang-Ming University, Taipei, Taiwan; National Yang-Ming University Hospital, Taiwan.
authors.forename: Hsi-Feng
authors.initials: HF
authors.lastname: Tu
authors.affiliation: Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Cheng-Hsien
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hsiu-Chuan
authors.initials: HC
authors.lastname: Chang
authors.affiliation: School of Dentistry, National Yang-Ming University, Taipei, Taiwan; Oral and Maxillofacial Surgery Section, Chi Mei Hospital, Liouying, Taiwan.
authors.forename: Wei-Fan
authors.initials: WF
authors.lastname: Chiang
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Nai-Chia
authors.initials: NC
authors.lastname: Shih
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yong-Syu
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: sykao@vghtpe.gov.tw.
authors.forename: Shou-Yen
authors.initials: SY
authors.lastname: Kao
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan; School of Dentistry, National Yang-Ming University, Taipei, Taiwan; Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: ckcw@ym.edu.tw.
authors.forename: Kuo-Wei
authors.initials: KW
authors.lastname: Chang
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology*; D002945:Cisplatin / Q000627:therapeutic use*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000473:pathology*; D066257:Heparin-binding EGF-like Growth Factor / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D066257:Heparin-binding EGF-like Growth Factor; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D002945:Cisplatin
keywords: COX-2; Cisplatin; HB-EGF; HNSCC; PGE2