The RARS-MAD1L1 Fusion Gene Induces Cancer Stem Cell-like Properties and Therapeutic Resistance in Nasopharyngeal Carcinoma

Clin Cancer Res. 2018 Feb 1;24(3):659-673. doi: 10.1158/1078-0432.CCR-17-0352. Epub 2017 Nov 13.


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. Clin Cancer Res; 24(3); 659-73. ©2017 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine-tRNA Ligase / genetics*
  • Arginine-tRNA Ligase / metabolism
  • Biomarkers, Tumor
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics*
  • Gene Knockdown Techniques
  • Gene Rearrangement
  • Humans
  • In Situ Hybridization, Fluorescence
  • Mice
  • Nasopharyngeal Carcinoma / diagnosis
  • Nasopharyngeal Carcinoma / genetics*
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Oncogene Proteins, Fusion*
  • Promoter Regions, Genetic
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / genetics


  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • MAD1L1 protein, human
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins c-myc
  • Arginine-tRNA Ligase