Identification of TRA2B-DNAH5 fusion as a novel oncogenic driver in human lung squamous cell carcinoma
Identification of TRA2B-DNAH5 fusion as a novel oncogenic driver in human lung squamous cell carcinoma
复制标题
鉴定 TRA2B-DNAH5 融合作为人肺鳞状细胞癌的新型致癌驱动因素。
DOI：
10.1038/cr.2016.111
复制
发表时间：
2016-10-01
期刊：
影响因子：
44.1
通讯作者：
Ji, Hongbin
中科院分区：
文献类型：
--
作者：
Li, Fei;Fang, Zhaoyuan;Ji, Hongbin
肺鳞癌(SCC)是肺癌的主要亚型之一。与肺腺癌(ADC)相比，我们目前对这一特定亚型肺癌的致癌驱动因素的了解很有限。通过外显子阵列分析、分子分析和功能研究，我们在这里确定TRA2B-DNAH5融合是肺鳞状细胞癌中一种新的致癌驱动因素。我们发现该基因融合仅见于肺鳞状细胞癌(3.1%，5/163)，而不存在于肺ADC(0/119)。通过机制研究，我们进一步揭示这种TRA2B-DNAH5融合通过调节SIRT6-ERK1/2-MMP1信号轴促进肺鳞状细胞癌恶性进展。我们发现，使用selumetinib抑制ERK1/2的激活可以有效地抑制TRA2B-DNAH5融合表达的肺鳞状细胞癌的生长。这些发现提高了我们目前对肺鳞状细胞癌致癌因素的认识，并为TRA2B-DNAH5融合的肺鳞状细胞癌患者提供了一种潜在的治疗策略。
Lung squamous cell carcinoma (SCC) is one of the major subtypes of lung cancer. Our current knowledge of oncogenic drivers in this specific subtype of lung cancer is largely limited compared with lung adenocarcinoma (ADC). Through exon array analyses, molecular analyses and functional studies, we here identify the TRA2B-DNAH5 fusion as a novel oncogenic driver in lung SCC. We found that this gene fusion occurs exclusively in lung SCC (3.1%, 5/163), but not in lung ADC (0/119). Through mechanistic studies, we further revealed that this TRA2B-DNAH5 fusion promotes lung SCC malignant progression through regulating a SIRT6-ERK1/2-MMP1 signaling axis. We show that inhibition of ERK1/2 activation using selumetinib efficiently inhibits the growth of lung SCC with TRA2B-DNAH5 fusion expression. These findings improve our current knowledge of oncogenic drivers in lung SCC and provide a potential therapeutic strategy for lung SCC patients with TRA2B-DNAH5 fusion.