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Aberrantly activated AREG–EGFR signaling is required for the growth and survival of CRTC1–MAML2 fusion-positive mucoepidermoid carcinoma cells

Oncogene volume 33, pages 3869–3877 (2014)Cite this article

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Abstract

Salivary gland tumors (SGT) are a group of highly heterogeneous head and neck malignancies with widely varied clinical outcomes and no standard effective treatments. The CRTC1–MAML2 fusion oncogene, encoded by a recurring chromosomal translocation t(11;19)(q14-21;p12-13), is a frequent genetic alteration found in >50% of mucoepidermoid carcinomas (MEC), the most common malignant SGT. In this study, we aimed to define the role of the CRTC1–MAML2 oncogene in the maintenance of MEC tumor growth and to investigate critical downstream target genes and pathways for therapeutic targeting of MEC. By performing gene expression analyses and functional studies via RNA interference and pharmacological modulation, we determined the importance of the CRTC1–MAML2 fusion gene and its downstream AREG–EGFR signaling in human MEC cancer cell growth and survival in vitro and in vivo using human MEC xenograft models. We found that CRTC1–MAML2 fusion oncogene was required for the growth and survival of fusion-positive human MEC cancer cells in vitro and in vivo. The CRTC1–MAML2 oncoprotein induced the upregulation of the epidermal growth factor receptor (EGFR) ligand Amphiregulin (AREG) by co-activating the transcription factor CREB, and AREG subsequently activated EGFR signaling in an autocrine manner that promoted MEC cell growth and survival. Importantly, CRTC1–MAML2-positive MEC cells were highly sensitive to EGFR signaling inhibition. Therefore, our study revealed that aberrantly activated AREG–EGFR signaling is required for CRTC1–MAML2-positive MEC cell growth and survival, suggesting that EGFR-targeted therapies will benefit patients with advanced, unresectable CRTC1–MAML2-positive MEC.

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Acknowledgements

We thank Marda Jorgensen for helping with immunohistochemical staining, Mei Zhang for helping with FACS analysis, and the Salivary Gland Tumor Biorepository (SGTB) for providing tumor specimens for this study. L Wu was supported by the University of Florida Shands Cancer Center Startup fund, Bankhead Coley Cancer Research Program, and the V foundation for Cancer Research.

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Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL, USA

    Z Chen, Y Gu, C Hu, S Lin & L Wu

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    J Chen & J D Griffin

  3. Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, FL, USA

    J-L Li

  4. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China

    H Shen

  5. Department of Medicine, Shands Cancer Center, University of Florida, Gainesville, FL, USA

    C Cao, R Gao & F J Kaye

  6. Teaching Hospital of Fujian Medical University, Fujian Province Tumor Hospital, Fuzhou, Fujian, China

    J Li

  7. Department of Otolaryngology, Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    P K Ha

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  1. Z Chen
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Correspondence to L Wu.

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Chen, Z., Chen, J., Gu, Y. et al. Aberrantly activated AREG–EGFR signaling is required for the growth and survival of CRTC1–MAML2 fusion-positive mucoepidermoid carcinoma cells. Oncogene 33, 3869–3877 (2014). https://doi.org/10.1038/onc.2013.348

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