TCRP1 transcriptionally regulated by c-Myc confers cancer chemoresistance in tongue and lung cancer.
TCRP1 transcriptionally regulated by c-Myc confers cancer chemoresistance in tongue and lung cancer.
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c-Myc 转录调控的 TCRP1 赋予舌癌和肺癌化疗耐药性
DOI：
10.1038/s41598-017-03763-0
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发表时间：
2017-06-16
影响因子：
4.6
通讯作者：
He Z
中科院分区：
文献类型：
--
作者：
Jia X;Zhang Z;Luo K;Zheng G;Lu M;Song Y;Liu H;Qiu H;He Z
以前，我们克隆了一个新的基因，称为“舌癌耐药相关蛋白1”（TCRP 1），它调节肿瘤的发生，增强顺铂（cDDP）在癌症中的耐药性，并可能是一个潜在的目标逆转耐药性。然而，调节TCRP 1表达的机制仍不清楚。在此，我们结合生物信息学分析，荧光素酶报告基因分析和ChIP分析，以确定c-Myc可以直接结合TCRP 1启动子，上调其表达。多药耐药舌癌细胞（Tca 8113/PYM）和顺铂耐药A549肺癌细胞（A549/DDP）中的TCRP 1上调伴随着c-Myc上调，与各自的亲本细胞相比。在舌癌和肺癌细胞中，siRNA介导的c-Myc敲低导致TCRP 1表达降低，而过表达c-Myc则相反。此外，TCRP 1敲低减弱了c-Myc过表达引起的化疗耐药性，但TCRP 1过表达削弱了c-Myc敲低对化疗敏感性的影响。此外，在人舌癌和肺癌组织中，c-Myc蛋白表达与TCRP 1蛋白表达呈正相关，这些蛋白水平与患者的预后不良相关。结合，这些发现表明，c-Myc可以在细胞系和临床样品中转录调节TCRP 1，并将c-Myc-TCRP 1轴鉴定为舌癌和肺癌预后的阴性生物标志物。
Previously, we cloned a new gene termed ‘tongue cancer resistance-associated protein 1’ (TCRP1), which modulates tumorigenesis, enhances cisplatin (cDDP) resistance in cancers, and may be a potential target for reversing drug resistance. However, the mechanisms for regulating TCRP1 expression remain unclear. Herein, we combined bioinformatics analysis with luciferase reporter assay and ChIP assay to determine that c-Myc could directly bind to TCRP1 promoter to upregulate its expression. TCRP1 upregulation in multidrug resistant tongue cancer cells (Tca8113/PYM) and cisplatin-resistant A549 lung cancer cells (A549/DDP) was accompanied by c-Myc upregulation, compared to respective parental cells. In tongue and lung cancer cells, siRNA-mediated knockdown of c-Myc led to decrease TCRP1 expression, whereas overexpression c-Myc did the opposite. Moreover, TCRP1 knockdown attenuated chemoresistance resulting from c-Myc overexpression, but TCRP1 overexpression impaired the effect of c-Myc knockdown on chemosensitivity. Additionally, in both human tongue and lung cancer tissues, c-Myc protein expression positively correlated with TCRP1 protein expression and these protein levels were associated with worse prognosis for patients. Combined, these findings suggest that c-Myc could transcriptionally regulate TCRP1 in cell lines and clinical samples and identified the c-Myc-TCRP1 axis as a negative biomarker of prognosis in tongue and lung cancers.