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

Z. Chen, J. Chen, Y. Gu, C. Hu, J. L. Li, S. Lin, H. Shen, C. Cao, R. Gao, J. Li, P. K. Ha, F. J. Kaye, J. D. Griffin, L. Wu

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3869-3877
Number of pages9
JournalOncogene
Volume33
Issue number29
DOIs
StatePublished - Jul 17 2014

Fingerprint

Mucoepidermoid Carcinoma
Epidermal Growth Factor Receptor
Survival
Growth
Oncogene Fusion
Cell Survival
Glandular and Epithelial Neoplasms
Mucoepidermoid Tumor
Autocrine Communication
Activating Transcription Factors
Amphiregulin
Neoplasms
Genetic Translocation
Gene Fusion
Oncogene Proteins
RNA Interference
Oncogenes
Heterografts
Neck
Up-Regulation

Keywords

  • AREG
  • CRTC1-MAML2
  • EGFR
  • mucoepidermoid carcinoma
  • salivary gland tumors

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Aberrantly activated AREG-EGFR signaling is required for the growth and survival of CRTC1-MAML2 fusion-positive mucoepidermoid carcinoma cells. / Chen, Z.; Chen, J.; Gu, Y.; Hu, C.; Li, J. L.; Lin, S.; Shen, H.; Cao, C.; Gao, R.; Li, J.; Ha, P. K.; Kaye, F. J.; Griffin, J. D.; Wu, L.

In: Oncogene, Vol. 33, No. 29, 17.07.2014, p. 3869-3877.

Research output: Contribution to journalArticle

Chen, Z, Chen, J, Gu, Y, Hu, C, Li, JL, Lin, S, Shen, H, Cao, C, Gao, R, Li, J, Ha, PK, Kaye, FJ, Griffin, JD & Wu, L 2014, 'Aberrantly activated AREG-EGFR signaling is required for the growth and survival of CRTC1-MAML2 fusion-positive mucoepidermoid carcinoma cells', Oncogene, vol. 33, no. 29, pp. 3869-3877. https://doi.org/10.1038/onc.2013.348
Chen, Z. ; Chen, J. ; Gu, Y. ; Hu, C. ; Li, J. L. ; Lin, S. ; Shen, H. ; Cao, C. ; Gao, R. ; Li, J. ; Ha, P. K. ; Kaye, F. J. ; Griffin, J. D. ; Wu, L. / Aberrantly activated AREG-EGFR signaling is required for the growth and survival of CRTC1-MAML2 fusion-positive mucoepidermoid carcinoma cells. In: Oncogene. 2014 ; Vol. 33, No. 29. pp. 3869-3877.
@article{834d565aa8b94fbda9a19d10b1221a24,
title = "Aberrantly activated AREG-EGFR signaling is required for the growth and survival of CRTC1-MAML2 fusion-positive mucoepidermoid carcinoma cells",
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.",
keywords = "AREG, CRTC1-MAML2, EGFR, mucoepidermoid carcinoma, salivary gland tumors",
author = "Z. Chen and J. Chen and Y. Gu and C. Hu and Li, {J. L.} and S. Lin and H. Shen and C. Cao and R. Gao and J. Li and Ha, {P. K.} and Kaye, {F. J.} and Griffin, {J. D.} and L. Wu",
year = "2014",
month = "7",
day = "17",
doi = "10.1038/onc.2013.348",
language = "English (US)",
volume = "33",
pages = "3869--3877",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "29",

}

TY - JOUR

T1 - Aberrantly activated AREG-EGFR signaling is required for the growth and survival of CRTC1-MAML2 fusion-positive mucoepidermoid carcinoma cells

AU - Chen, Z.

AU - Chen, J.

AU - Gu, Y.

AU - Hu, C.

AU - Li, J. L.

AU - Lin, S.

AU - Shen, H.

AU - Cao, C.

AU - Gao, R.

AU - Li, J.

AU - Ha, P. K.

AU - Kaye, F. J.

AU - Griffin, J. D.

AU - Wu, L.

PY - 2014/7/17

Y1 - 2014/7/17

N2 - 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.

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.

KW - AREG

KW - CRTC1-MAML2

KW - EGFR

KW - mucoepidermoid carcinoma

KW - salivary gland tumors

UR - http://www.scopus.com/inward/record.url?scp=84904598609&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84904598609&partnerID=8YFLogxK

U2 - 10.1038/onc.2013.348

DO - 10.1038/onc.2013.348

M3 - Article

C2 - 23975434

AN - SCOPUS:84904598609

VL - 33

SP - 3869

EP - 3877

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 29

ER -