CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to erlotinib via transcriptional regulation of EGFR.
CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to erlotinib via transcriptional regulation of EGFR.
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CUL4A 过表达可促进肺癌生长，并通过 EGFR 的转录调节使肺癌细胞对厄洛替尼敏感。
DOI：
10.1186/1476-4598-13-252
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发表时间：
2014-11-21
期刊：
影响因子：
37.3
通讯作者：
Wei G
中科院分区：
文献类型：
--
作者：
Wang Y;Zhang P;Liu Z;Wang Q;Wen M;Wang Y;Yuan H;Mao JH;Wei G
CUL4A已被认为是几种人类癌症的致癌基因，但其在人类非小细胞肺癌（NSCLC）中的临床意义和功能作用尚不清楚。采用RT-PCR和Western blot检测CUL4A的表达水平。CUL4A的强制表达由逆转录病毒介导，CUL4A的沉默由表达慢病毒的shrna介导。在体外和体内分别用MTT法测定肺癌细胞的生长能力。我们发现CUL4A在人肺癌组织和肺癌细胞系中高表达，并且这种高表达与疾病进展和预后呈正相关。CUL4A在人肺癌细胞系中的过表达增加了细胞增殖，抑制了细胞凋亡，并随后赋予了化疗耐药性。另一方面，在肿瘤异种移植模型中，沉默非小细胞肺癌CUL4A表达可降低细胞增殖，促进细胞凋亡，抑制肿瘤生长。在机制上，我们发现CUL4A调节EGFR的转录表达和激活，随后激活AKT。靶向抑制EGFR活性可阻断CUL4A诱导的这些致癌活性。我们的研究结果强调了CUL4A在NSCLC中的重要意义，提示CUL4A可能是一个有希望的治疗靶点，也是NSCLC患者预后和EGFR靶向治疗的潜在生物标志物。本文的在线版本（doi:10.1186/1476-4598-13-252）包含补充材料，可供授权用户使用。
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. 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. 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. 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. The online version of this article (doi:10.1186/1476-4598-13-252) contains supplementary material, which is available to authorized users.
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影响因子：
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作者：
Noto, Alessia;De Vitis, Claudia;Ciliberto, Gennaro
通讯作者：
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影响因子：
4.8
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4.8
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影响因子：
5.3
作者：
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通讯作者：
You L