PMID- 23975434 OWN - NLM STAT- MEDLINE DCOM- 20140919 LR - 20220310 IS - 1476-5594 (Electronic) IS - 0950-9232 (Linking) VI - 33 IP - 29 DP - 2014 Jul 17 TI - Aberrantly activated AREG-EGFR signaling is required for the growth and survival of CRTC1-MAML2 fusion-positive mucoepidermoid carcinoma cells. PG - 3869-77 LID - 10.1038/onc.2013.348 [doi] AB - 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. FAU - Chen, Z AU - Chen Z AD - Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL, USA. FAU - Chen, J AU - Chen J AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. FAU - Gu, Y AU - Gu Y AD - Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL, USA. FAU - Hu, C AU - Hu C AD - Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL, USA. FAU - Li, J-L AU - Li JL AUID- ORCID: 000000026487081X AD - Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, FL, USA. FAU - Lin, S AU - Lin S AD - Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL, USA. FAU - Shen, H AU - Shen H AD - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China. FAU - Cao, C AU - Cao C AD - Department of Medicine, Shands Cancer Center, University of Florida, Gainesville, FL, USA. FAU - Gao, R AU - Gao R AD - Department of Medicine, Shands Cancer Center, University of Florida, Gainesville, FL, USA. FAU - Li, J AU - Li J AD - Teaching Hospital of Fujian Medical University, Fujian Province Tumor Hospital, Fuzhou, Fujian, China. FAU - Ha, P K AU - Ha PK AD - Department of Otolaryngology, Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. FAU - Kaye, F J AU - Kaye FJ AD - Department of Medicine, Shands Cancer Center, University of Florida, Gainesville, FL, USA. FAU - Griffin, J D AU - Griffin JD AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. FAU - Wu, L AU - Wu L AD - Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL, USA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130826 PL - England TA - Oncogene JT - Oncogene JID - 8711562 RN - 0 (AREG protein, human) RN - 0 (Amphiregulin) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (CRTC1 protein, human) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (DNA-Binding Proteins) RN - 0 (EGF Family of Proteins) RN - 0 (Glycoproteins) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (MAML2 protein, human) RN - 0 (Nuclear Proteins) RN - 0 (Oncogene Proteins, Fusion) RN - 0 (Trans-Activators) RN - 0 (Transcription Factors) RN - EC 2.7.10.1 (ErbB Receptors) RN - PQX0D8J21J (Cetuximab) SB - IM MH - Amphiregulin MH - Animals MH - Antibodies, Monoclonal, Humanized/pharmacology MH - Carcinoma, Mucoepidermoid/*genetics/*metabolism MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Cell Survival/drug effects/genetics MH - Cetuximab MH - Chromosomes, Human, Pair 11 MH - Chromosomes, Human, Pair 19 MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - DNA-Binding Proteins/*genetics MH - Disease Models, Animal MH - EGF Family of Proteins MH - ErbB Receptors/antagonists & inhibitors/*metabolism MH - Female MH - Gene Expression Regulation, Neoplastic MH - Glycoproteins/genetics/*metabolism MH - Heterografts MH - Humans MH - Intercellular Signaling Peptides and Proteins/genetics/*metabolism MH - Nuclear Proteins/*genetics MH - Oncogene Proteins, Fusion/*genetics/metabolism MH - Protein Binding MH - *Signal Transduction/drug effects MH - Trans-Activators MH - Transcription Factors/*genetics MH - Transcriptional Activation MH - Translocation, Genetic EDAT- 2013/08/27 06:00 MHDA- 2014/09/23 06:00 CRDT- 2013/08/27 06:00 PHST- 2012/11/15 00:00 [received] PHST- 2013/07/08 00:00 [revised] PHST- 2013/07/23 00:00 [accepted] PHST- 2013/08/27 06:00 [entrez] PHST- 2013/08/27 06:00 [pubmed] PHST- 2014/09/23 06:00 [medline] AID - onc2013348 [pii] AID - 10.1038/onc.2013.348 [doi] PST - ppublish SO - Oncogene. 2014 Jul 17;33(29):3869-77. doi: 10.1038/onc.2013.348. Epub 2013 Aug 26.