title: CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to erlotinib via transcriptional regulation of EGFR.
abstract: BACKGROUND
  CUL4A has been proposed as oncogene in several types of human cancer, but its clinical significance and functional role in human non-small cell lung cancer (NSCLC) remain unclear.
  
  
  METHODS
  Expression level of CUL4A was examined by RT-PCR and Western blot. Forced expression of CUL4A was mediated by retroviruses, and CUL4A silencing by shRNAs expressing lentiviruses. Growth capacity of lung cancer cells was measured by MTT in vitro and tumorigenesis in vivo, respectively.
  
  
  RESULTS
  We found that CUL4A was highly expressed in human lung cancer tissues and lung cancer cell lines, and this elevated expression positively correlated with disease progression and prognosis. Overexpression of CUL4A in human lung cancer cell lines increased cell proliferation, inhibited apoptosis, and subsequently conferred resistance to chemotherapy. On other hand, silencing CUL4A expression in NSCLC cells reduced proliferation, promoted apoptosis and resulted in tumor growth inhibition in cancer xenograft model. Mechanistically, we revealed CUL4A regulated EGFR transcriptional expression and activation, and subsequently activated AKT. Targeted inhibition of EGFR activity blocked these CUL4A induced oncogenic activities.
  
  
  CONCLUSIONS
  Our results highlight the significance of CUL4A in NSCLC and suggest that CUL4A could be a promising therapy target and a potential biomarker for prognosis and EGFR target therapy in NSCLC patients.
authors.forename: Yunshan
authors.initials: Y
authors.lastname: Wang
authors.forename: Pengju
authors.initials: P
authors.lastname: Zhang
authors.forename: Ziming
authors.initials: Z
authors.lastname: Liu
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Mingxin
authors.initials: M
authors.lastname: Wen
authors.forename: Yuli
authors.initials: Y
authors.lastname: Wang
authors.forename: Hongtu
authors.initials: H
authors.lastname: Yuan
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.affiliation: Department of Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, P,R, China. gwwei@yahoo.com.
authors.forename: Guangwei
authors.initials: G
authors.lastname: Wei
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D044842:Cullin Proteins / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D011799:Quinazolines / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics
chemical_list: C114234:CUL4A protein, human; D044842:Cullin Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors