Abstract
Chromosomal rearrangements that facilitate tumor formation and progression through activation of oncogenic tyrosine kinases are frequently observed in cancer. The ETV6-NTRK3 (EN) fusion has been implicated in various cancers, including infantile fibrosarcoma, secretory breast carcinoma, and acute myeloblastic leukemia, and has exhibited in vivo and in vitro transforming ability. In the present study, we analyzed transcriptome alterations using DNA microarray and RNA-Seq in EN-transduced NIH3T3 fibroblasts to identify the mechanisms that are involved in EN-mediated tumorigenesis. Through functional profile assessment of EN-regulated transcriptome alterations, we found that upregulated genes by EN were mainly associated with cell motion, membrane invagination, and cell proliferation, while downregulated genes were involved in cell adhesion, which correlated with the transforming potential and increased proliferation in EN-transduced cells. KEGG pathway analysis identified the JAK-STAT signaling pathway with the highest statistical significance. Moreover, Ingenuity Pathway Analysis and gene regulatory network analysis identified the STAT1 transcription factor and its target genes as top EN-regulated molecules. We further demonstrated that EN enhanced STAT1 phosphorylation but attenuated STAT1 acetylation, eventually inhibiting the interaction between the NF-κB p65 subunit and acetylated STAT1. Consequently, nuclear translocation of NF-κB p65 and subsequent NF-κB activity were increased by EN. Notably, inhibition of STAT1 phosphorylation attenuated tumorigenic ability of EN in vitro and in vivo. Taken together, here we report, for the first time, STAT1 as a significant EN-regulated transcription factor and a crucial mediator of EN-induced tumorigenesis.
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Acknowledgements
We thank Dr. Jin Muk Kang for critical review of the manuscript.
Funding
This work was supported by a National Research Foundation grant of Korea (NRF-2014M3A9B5073918), a National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (1520120) funded by the Korean government, and the British Columbia Cancer Foundation through generous donations from Team Finn and the Ride to Conquer Cancer (to PHS).
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Park, J., Kim, J., Park, B. et al. Novel identification of STAT1 as a crucial mediator of ETV6-NTRK3-induced tumorigenesis. Oncogene 37, 2270–2284 (2018). https://doi.org/10.1038/s41388-017-0102-2
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DOI: https://doi.org/10.1038/s41388-017-0102-2
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