TY - JOUR
T1 - The RARS–MAD1L1 fusion gene induces cancer stem cell–like properties and therapeutic resistance in nasopharyngeal carcinoma
AU - Zhong, Qian
AU - Liu, Zhi Hua
AU - Lin, Zhi Rui
AU - Hu, Ze Dong
AU - Yuan, Li
AU - Liu, Yan Min
AU - Zhou, Ai Jun
AU - Xu, Li Hua
AU - Hu, Li Juan
AU - Wang, Zi Feng
AU - Guan, Xin Yuan
AU - Hao, Jia Jie
AU - Lui, Vivian W.Y.
AU - Guo, Ling
AU - Mai, Hai Qiang
AU - Chen, Ming Yuan
AU - Han, Fei
AU - Xia, Yun Fei
AU - Grandis, Jennifer R.
AU - Zhang, Xing
AU - Zeng, Mu Sheng
N1 - Funding Information:
This work was supported by the grants from National Key R&D Program of China (2017YFA0505600-04, to M.-S. Zeng), the Ministry of Science and Technology of China (2013CB910500 and 2015AA020931; to X. Zhang and Q. Zhong), the National Natural Science Foundation of China (81230045, 91440106, 81161120408, 81572600, 81772883, 81372244, 81772877, 81572848 and 81520108022, to M.-S. Zeng, L. Guo, and Q. Zhong), the Science and Technology project of Guangdong Province (2014B050504004, 2015B050501005, to M.-S. Zeng), the talent program of Guangdong Province
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - Purpose: Nasopharyngeal carcinoma (NPC) is the most common head and neck cancer in Southeast Asia. Because local recurrence and distant metastasis are still the main causes of NPC treatment failure, it is urgent to identify new tumor markers and therapeutic targets for advanced NPC. Experimental Design: RNA sequencing (RNA-seq) was applied to look for interchromosome translocation in NPC. PCR, FISH, and immunoprecipitation were used to examine the fusion gene expression at RNA, DNA, and protein levels in NPC biopsies. MTT assay, colony formation assay, sphere formation assay, co-immunoprecipitation, chromatin immunoprecipitation assay, and in vivo chemoresistance assay were applied to explore the function of RARS-MAD1L1 in NPC. Results: We demonstrated that RARS-MAD1L1 was present in 10.03% (35/349) primary NPC biopsies and 10.7% (9/84) in head and neck cancer (HNC) samples. RARS-MAD1L1 overexpression increased cell proliferation, colony formation, and tumorigenicity in vitro, and the silencing of endogenous RARS-MAD1L1 reduced cancer cell growth and colony formation in vitro. In addition, RARS-MAD1L1 increased the side population (SP) ratio and induced chemo- and radioresistance. Furthermore RARS-MAD1L1 interacted with AIMP2, which resulted in activation of FUBP1/c-Myc pathway. The silencing of FUBP1 or the administration of a c-Myc inhibitor abrogated the cancer stem cell (CSC)-like characteristics induced by RARS-MAD1L1. The expression of c-Myc and ABCG2 was higher in RARS-MAD1L1–positive HNC samples than in negative samples. Conclusions: Our findings indicate that RARS-MAD1L1 might contribute to tumorigenesis, CSC-like properties, and therapeutic resistance, at least in part, through the FUBP1/c-Myc axis, implying that RARS-MAD1L1 might serve as an attractive target for therapeutic intervention for NPC.
AB - Purpose: Nasopharyngeal carcinoma (NPC) is the most common head and neck cancer in Southeast Asia. Because local recurrence and distant metastasis are still the main causes of NPC treatment failure, it is urgent to identify new tumor markers and therapeutic targets for advanced NPC. Experimental Design: RNA sequencing (RNA-seq) was applied to look for interchromosome translocation in NPC. PCR, FISH, and immunoprecipitation were used to examine the fusion gene expression at RNA, DNA, and protein levels in NPC biopsies. MTT assay, colony formation assay, sphere formation assay, co-immunoprecipitation, chromatin immunoprecipitation assay, and in vivo chemoresistance assay were applied to explore the function of RARS-MAD1L1 in NPC. Results: We demonstrated that RARS-MAD1L1 was present in 10.03% (35/349) primary NPC biopsies and 10.7% (9/84) in head and neck cancer (HNC) samples. RARS-MAD1L1 overexpression increased cell proliferation, colony formation, and tumorigenicity in vitro, and the silencing of endogenous RARS-MAD1L1 reduced cancer cell growth and colony formation in vitro. In addition, RARS-MAD1L1 increased the side population (SP) ratio and induced chemo- and radioresistance. Furthermore RARS-MAD1L1 interacted with AIMP2, which resulted in activation of FUBP1/c-Myc pathway. The silencing of FUBP1 or the administration of a c-Myc inhibitor abrogated the cancer stem cell (CSC)-like characteristics induced by RARS-MAD1L1. The expression of c-Myc and ABCG2 was higher in RARS-MAD1L1–positive HNC samples than in negative samples. Conclusions: Our findings indicate that RARS-MAD1L1 might contribute to tumorigenesis, CSC-like properties, and therapeutic resistance, at least in part, through the FUBP1/c-Myc axis, implying that RARS-MAD1L1 might serve as an attractive target for therapeutic intervention for NPC.
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U2 - 10.1158/1078-0432.CCR-17-0352
DO - 10.1158/1078-0432.CCR-17-0352
M3 - Article
C2 - 29133573
AN - SCOPUS:85041463297
SN - 1078-0432
VL - 24
SP - 659
EP - 673
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3
ER -