Abstract
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.
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Acknowledgements
We thank Drs Lei Zhang, Xiumin Yan, Zhuang Wei, Shuai Wu, Lin Pan and Liang Dong for technical supports. We thank Dangsheng Li for the critical reading of the manuscript and suggestions. We also thank all of our lab members for helpful discussion. This work was supported by the Ministry of Science and Technology of China (2012CB910800), the National Natural Science Foundation of China (81430066, 81402276, 81402371, 81401898, 81402498, 81101583, 81372509, 31370747 and 81325015), the Science and Technology Commission of Shanghai Municipality (12JC1409800, 15XD1504000), the “Cross and cooperation in science and technology innovation team” program, the Chinese Postdoctoral foundation (2014M561536, 2013T60476), the Shanghai Postdoctoral Foundation (14R21411400), and the Shanghai Institutes for Biological Sciences (2013KIP303, 2013KIP102, 2014KIP304).
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Supplementary information
Supplementary information, Table S1
409 potential gene fusions or isoforms in ADCs. (XLS 53 kb)
Supplementary information, Table S2
284 potential gene fusions or isoforms in SCCs. (XLS 43 kb)
Supplementary information, Table S3
Clinical features of 5 lung SCC patients harboring TRA2B-DNAH5 fusion (PDF 8 kb)
Supplementary information, Table S4
Identification of TRA2B-DNAH5 fusion interacting proteins IP-MS analyses. (XLS 24 kb)
Supplementary information, Table S5
The list of primers used for real-time PCR quantification in this study. (PDF 19 kb)
Supplementary information, Figure S1
Identification of TIE1 fusion in human lung ADC. (PDF 172 kb)
Supplementary information, Figure S2
Identification of genomic breakpoint of TRA2B-DNAH5 fusion. (PDF 153 kb)
Supplementary information, Figure S3
Sanger sequencing confirms the TRA2B-DNAH5 fusion in another 4 human lung SCC specimensat RNA level. (PDF 122 kb)
Supplementary information, Figure S4
The TRA2B-DNAH5 fusion promotes cell transformation. (PDF 51 kb)
Supplementary information, Figure S5
Immunohistochemical studies of CRL-5889 xenograft tumors. (PDF 154 kb)
Supplementary information, Figure S6
Confirmation of MMP1 up-regulation and ERK1/2 activation in cells and xenograft tumors. (PDF 166 kb)
Supplementary information, Figure S7
Up-regulated MMP1 expression mediates the promotive function of TRA2B-DNAH5 fusion in cell invasion and migration. (PDF 142 kb)
Supplementary information, Figure S8
Knockdown of MMP1 significantly inhibits the tumor-promotivefunction of the TRA2B-DNAH5 fusion in CRL-5889 xenograft assay. (PDF 114 kb)
Supplementary information, Figure S9
Human lung SCC specimens harboring the TRA2B-DNAH5 fusion are stained positive for p-ERK1/2 and MMP1. (PDF 172 kb)
Supplementary information, Figure S10
TRA2B-DNAH5 fusion is mainlylocated at cytoplasm. (PDF 52 kb)
Supplementary information, Figure S11
CHIP-Seq data reveals the binding of SIRT6 on TIAM1, SUV620H1 and RIN1 genes. (PDF 71 kb)
Supplementary information, Figure S12
IGF1R may be involved in the activation of MEK1/2 and up-regulation of MMP1 by TRA2B-DNAH5 fusion. (PDF 75 kb)
Supplementary information, Figure S13
Human lung SCC cells expressing the TRA2B-DNAH5 fusion are more sensitive to selumetinib treatment. (PDF 118 kb)
Supplementary information, Figure S14
Selumetinib treatment inhibits ERK1/2 activity and MMP1 levels in CRL-5889 xenograft tumors with TRA2B-DNAH5 fusion expression. (PDF 164 kb)
Supplementary information, Figure S15
Selumetinib treatment doesn't cause a significant weight loss in mice. (PDF 112 kb)
Supplementary information, Figure S16
Marimastat treatment has no inhibitory effect on tumor growth of CRL-5889 xenograft tumors. (PDF 61 kb)
Supplementary information, Data S1
CDS sequence and amino acids sequence of TRA2B-DNAH5 fusion. (PDF 44 kb)
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Li, F., Fang, Z., Zhang, J. et al. Identification of TRA2B-DNAH5 fusion as a novel oncogenic driver in human lung squamous cell carcinoma. Cell Res 26, 1149–1164 (2016). https://doi.org/10.1038/cr.2016.111
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DOI: https://doi.org/10.1038/cr.2016.111
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