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

Molecular Cancer

Research

Guangwei Wei¹  Mingxin Wen¹  Yuli Wang¹  Yunshan Wang²  Qin Wang³  Pengju Zhang⁴  Ziming Liu⁵  Hongtu Yuan⁶  Jian-Hua Mao⁷ 

[1] Department of Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, 44 Wenhua Xi Road, 250012, Jinan, Shandong, P.R. China;Department of Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, 44 Wenhua Xi Road, 250012, Jinan, Shandong, P.R. China;Department of International Biotechnology R&D Center, Shandong University School of Ocean, 180 Wenhua Xi Road, 264209, Weihai, Shandong, P.R. China;Department of Anesthesiology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, 250012, Jinan, P.R. China;Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, 250012, Jinan, Shandong, P.R. China;Department of Neurosurgery, The Fifth People’s Hospital, 447 Jingshen Road, 250022, Jinan, P.R. China;Department of Pathology, Shandong Cancer Hospital and Institute, 250012, Jinan, P.R. China;Life Sciences Division, Lawrence Berkeley National Laboratory, 94127, Berkeley, CA, USA;

关键词: CUL4A;    Lung cancer;    EGFR;    Erlotinib;   

DOI  :  10.1186/1476-4598-13-252

 received in 2014-06-04, accepted in 2014-11-10,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundCUL4A 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.MethodsExpression 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.ResultsWe 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.ConclusionsOur 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.

【 授权许可】

Unknown   
© Wang et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.