CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to Erlotinib via transcriptional regulation of EGFR

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• 作者：Yunshan Wang (6) (7)
  Pengju Zhang (8)
  Ziming Liu (9)
  Qin Wang (10)
  Mingxin Wen (6)
  Yuli Wang (6)
  Hongtu Yuan (11)
  Jian-Hua Mao (12)
  Guangwei Wei (6)
  
  6. 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
  7. Department of International Biotechnology R&D Center ; Shandong University School of Ocean ; 180 Wenhua Xi Road ; Weihai ; Shandong ; 264209 ; P.R. China
  8. Department of Biochemistry and Molecular Biology ; Shandong University School of Medicine ; 44 Wenhua Xi Road ; Jinan ; Shandong ; 250012 ; P.R. China
  9. Department of Neurosurgery ; The Fifth People鈥檚 Hospital ; 447 Jingshen Road ; Jinan ; 250022 ; P.R. China
  10. Department of Anesthesiology ; Qilu Hospital ; Shandong University ; 107 Wenhua Xi Road ; Jinan ; 250012 ; P.R. China
  11. Department of Pathology ; Shandong Cancer Hospital and Institute ; Jinan ; 250012 ; P.R. China
  12. Life Sciences Division ; Lawrence Berkeley National Laboratory ; Berkeley ; CA ; 94127 ; USA
  
• 关键词：CUL4A ; Lung cancer ; EGFR ; Erlotinib
• 刊名：Molecular Cancer
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：13
• 期：1
• 全文大小：3,270 KB
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• 刊物主题：Cancer Research; Oncology;
• 出版者：BioMed Central
• ISSN：1476-4598

文摘

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.