Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma.
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Journal: 2015/September - Cancer Biology and Therapy
ISSN: 1555-8576
Abstract:
Nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies and exhibits regional differences in incidence. Because many fusion genes have been discovered in different types of tumors over the past few years, we aimed to investigate the existence of a fusion gene in primary NPC patients using RNA-seq. In this study, for the first time, we found that fibroblast growth factor receptor 3-transforming acidic coiled-coil-containing protein 3 (FGFR3-TACC3) fusion transcripts are recurrently detected in NPC. The presence of this fusion gene was also detected in head and neck cancer, esophageal squamous cell carcinoma (ESCC), and lung cancer. Furthermore, we found certain new isoforms of the FGFR3-TACC3 fusion transcripts, such as a gene fusion between exon 18 of FGFR3 and exon 6 or exon 14 of TACC3 and agene fusion between exon 19 of FGFR3 and exon 11 of TACC3. In addition, we showed that the FGFR3-TACC3 fusion gene promotes cell proliferation, colony formation, and transforming ability in vitro, whereas the FGFR3-TACC3 K508M mutant or treatment with the FGFR inhibitor PD173074 abrogates these effects, suggesting that FGFR3-TACC3 most likely exerts its effects through activation of FGFR kinase activity. This activation likely leads to the development of NPC. Additionally, FGFR3-TACC3 could trigger activation of the ERK and Akt signaling pathways, whereas FGFR3-TACC3 K508M mutant could not, suggesting that these 2 signaling pathways might be involved in the function of FGFR3-TACC3. Taken together, our data demonstrated the oncogenic role of FGFR3-TACC3 in vitro, indicating that FGFR3-TACC3 may be useful as a diagnostic marker and therapeutic target in cancers.
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Cancer Biol Ther 15(12): 1613-1621
PMID: 25535896

Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma

Abbreviations

FGFR3
fibroblast growth factor receptor 3
TACC3
transforming acidic coiled-coil-containing protein 3
NPC
nasopharyngeal carcinoma
LTBR
lymphotoxin β receptor
CCND1
cyclin D1
RT-PCR
reverse transcription-PCR
FBS
fetal bovine serum
MTT
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide
SDS
sodium dodecyl sulfate
DTT
DL-dithiothreitol
DMSO
dimethyl sulfoxide
PBS
phosphate-buffered saline
PI
propidium iodide
State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center; Guangzhou, China
Department of Experimental Research; Sun Yat-sen University Cancer Center; Guangzhou, China
Department of Oncology and Hematology; The First Affiliated Hospital of Guangzhou Medical University; Guangzhou, China
These authors equally contributed to this work.
Correspondence to: Mu-Sheng Zeng; Email: nc.ude.usys.liam@hsmgnez; Qian Zhong; Email: nc.gro.ccusys@naiqgnohz
Received 2014 Apr 30; Revised 2014 Aug 3; Accepted 2014 Sep 1.
Copyright © 2014 Taylor & Francis Group, LLC

Abstract

Nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies and exhibits regional differences in incidence. Because many fusion genes have been discovered in different types of tumors over the past few years, we aimed to investigate the existence of a fusion gene in primary NPC patients using RNA-seq. In this study, for the first time, we found that fibroblast growth factor receptor 3-transforming acidic coiled-coil-containing protein 3 (FGFR3-TACC3) fusion transcripts are recurrently detected in NPC. The presence of this fusion gene was also detected in head and neck cancer, esophageal squamous cell carcinoma (ESCC), and lung cancer. Furthermore, we found certain new isoforms of the FGFR3-TACC3 fusion transcripts, such as a gene fusion between exon 18 of FGFR3 and exon 6 or exon 14 of TACC3 and agene fusion between exon 19 of FGFR3 and exon 11 of TACC3. In addition, we showed that the FGFR3-TACC3 fusion gene promotes cell proliferation, colony formation, and transforming ability in vitro, whereas the FGFR3-TACC3 K508M mutant or treatment with the FGFR inhibitor PD173074 abrogates these effects, suggesting that FGFR3-TACC3 most likely exerts its effects through activation of FGFR kinase activity. This activation likely leads to the development of NPC. Additionally, FGFR3-TACC3 could trigger activation of the ERK and Akt signaling pathways, whereas FGFR3-TACC3 K508M mutant could not, suggesting that these 2 signaling pathways might be involved in the function of FGFR3-TACC3. Taken together, our data demonstrated the oncogenic role of FGFR3-TACC3 in vitro, indicating that FGFR3-TACC3 may be useful as a diagnostic marker and therapeutic target in cancers.

Keywords: FGFR3-TACC3, fusion gene, NPC, proliferation, tumorigenesis
Abstract

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