The RARS-MAD1L1 Fusion Gene Induces Cancer Stem Cell-like Properties and Therapeutic Resistance in Nasopharyngeal Carcinoma.
The RARS-MAD1L1 Fusion Gene Induces Cancer Stem Cell-like Properties and Therapeutic Resistance in Nasopharyngeal Carcinoma.
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RARS-MAD1L1 融合基因诱导鼻咽癌的癌症干细胞样特性和治疗耐药性。
DOI：
10.1158/1078-0432.ccr-17-0352
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发表时间：
2018-02-01
期刊：
影响因子：
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通讯作者：
Zeng MS
中科院分区：
文献类型：
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作者：
Zhong Q;Liu ZH;Lin ZR;Hu ZD;Yuan L;Liu YM;Zhou AJ;Xu LH;Hu LJ;Wang ZF;Guan XY;Hao JJ;Lui VWY;Guo L;Mai HQ;Chen MY;Han F;Xia YF;Grandis JR;Zhang X;Zeng MS
鼻咽癌是东南亚最常见的头颈癌。由于局部复发和远处转移仍是鼻咽癌治疗失败的主要原因，寻找新的肿瘤标记物和治疗靶点是治疗晚期鼻咽癌的迫切需要。应用RNA-SEQ技术寻找鼻咽癌的染色体易位。采用聚合酶链式反应、荧光原位杂交和免疫沉淀法检测鼻咽癌组织中融合基因在RNA、DNA和蛋白质水平的表达。采用四甲基偶氮唑盐比色法、集落形成实验、球体形成实验、共IP实验、芯片实验和体内耐药实验探讨RARS-MAD1L1在鼻咽癌中的作用。结果显示，10.03%(35/349)的鼻咽癌组织和10.7%(9/84)的头颈癌组织中存在RARS-MAD1L1。RARS-MAD1L1过表达在体外促进细胞增殖、集落形成和致瘤性，而抑制内源性RARS-MAD1L1抑制体外癌细胞生长和集落形成。此外，RARS-MAD1L1增加了副群体(SP)比率，并诱导了化疗和放射抗性。RARS-MAD1L1与AIMP2相互作用，激活FUBP1/c-Myc通路。沉默FUBP1或给予c-Myc抑制剂可取消RARS-MAD1L1诱导的肿瘤干细胞(CSC)样特征。RARS-MAD1L1阳性HNC中c-Myc和ABCG2的表达高于RARS-MAD1L1阴性HNC。我们的研究结果表明，RARS-MAD1L1可能至少部分通过FUBP1/c-Myc轴参与肿瘤的发生、CSC样特性和治疗耐药，提示RARS-MAD1L1可能是鼻咽癌治疗干预的一个有吸引力的靶点。
Nasopharyngeal carcinoma (NPC) is 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. 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-IP, ChIP assay, and in vivo chemoresistance assay were applied to explore the function of RARS-MAD1L1 in NPC. 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. Additionally, RARS-MAD1L1 increased the side population (SP) ratio and induced chemo- and radio-resistance. 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. 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.