Li Fei, Fang Zhaoyuan, Zhang Jian, Li Chen, Liu Hongyan, Xia Jufeng, Zhu Hongwen, Guo Chenchen, Qin Zhen, Li Fuming, Han Xiangkun, Wang Yuetong, Feng Yan, Wang Ye, Zhang Wenjing, Wang Zuoyun, Jin Yujuan, Sun Yihua, Wei Wenyi, Zeng Rong, Chen Haiquan, Ji Hongbin
Key Laboratory of Systems Biology, Shanghai 200031, China.
CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.
Cell Res. 2016 Oct;26(10):1149-1164. doi: 10.1038/cr.2016.111. Epub 2016 Sep 27.
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.
肺鳞状细胞癌（SCC）是肺癌的主要亚型之一。与肺腺癌（ADC）相比，我们目前对这种特定亚型肺癌中致癌驱动因素的了解在很大程度上是有限的。通过外显子阵列分析、分子分析和功能研究，我们在此确定TRA2B-DNAH5融合是肺SCC中的一种新型致癌驱动因素。我们发现这种基因融合仅发生在肺SCC中（3.1%，5/163），而在肺ADC中未发生（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SCC的恶性进展。我们表明，使用司美替尼抑制ERK1/2激活可有效抑制表达TRA2B-DNAH5融合的肺SCC的生长。这些发现增进了我们目前对肺SCC中致癌驱动因素的了解，并为具有TRA2B-DNAH5融合的肺SCC患者提供了一种潜在的治疗策略。
