Identification of TRA2B-DNAH5 fusion as a novel oncogenic driver in human lung squamous cell carcinoma.
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.
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
Fei
F
Li
Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Zhaoyuan
Z
Fang
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
Jian
J
Zhang
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.
Chen
C
Li
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.
Hongyan
H
Liu
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.
Jufeng
J
Xia
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
Hongwen
H
Zhu
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
Chenchen
C
Guo
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
Zhen
Z
Qin
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.
Fuming
F
Li
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.
Xiangkun
X
Han
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
Yuetong
Y
Wang
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.
Yan
Y
Feng
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.
Ye
Y
Wang
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
Wenjing
W
Zhang
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.
Zuoyun
Z
Wang
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.
Yujuan
Y
Jin
Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Yihua
Y
Sun
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Wenyi
W
Wei
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|School of Life Science and Technology, Shanghai Tech University, Shanghai 200120, China.
Rong
R
Zeng
Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Haiquan
H
Chen
Key Laboratory of Systems Biology, Shanghai 200031, China.|CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.|Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China.|School of Life Science and Technology, Shanghai Tech University, Shanghai 200120, China.
Hongbin
H
Ji
D000818:Animals; D056444:Axonemal Dyneins / Q000235:genetics*; D001562:Benzimidazoles / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D050939:Gene Fusion; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors / Q000235:genetics*; D015398:Signal Transduction; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1 / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
C517975:AZD 6244; D001562:Benzimidazoles; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D015514:Oncogene Proteins, Fusion; C092117:RIN1 protein, human; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C097083:TRA2B protein, human; D000068103:Serine-Arginine Splicing Factors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020781:Matrix Metalloproteinase 1; C516592:SIRT6 protein, human; D037761:Sirtuins; D056444:Axonemal Dyneins; C497507:DNAH5 protein, human
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