Meng Xiangfeng, Sun Wu, Yu Jing, Zhou Yu, Gu Yuanyuan, Han Jiayi, Zhou Likun, Jiang Xiaohong, Wang Chen
State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu 210046, China.
The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing, Jiangsu 210008, China.
Mol Ther Nucleic Acids. 2020 Oct 15;22:1004-1015. doi: 10.1016/j.omtn.2020.10.018. eCollection 2020 Dec 4.
Oxaliplatin resistance is a major challenge in the clinical treatment for advanced colorectal cancer (CRC). Long non-coding RNAs (lncRNAs) are involved in tumorigenesis and progression as critical regulators, while their potential roles in chemoresistance are poorly understood. In this study, we report that the LINC00460-miR-149-5p/miR-150-5p-mutant p53 feedback loop is responsible for oxaliplatin resistance in CRC. First, LINC00460 was found to exhibit higher expression in oxaliplatin-resistant CRC (CRC/OxR) cells compared with parental oxaliplatin-sensitive ones, and this expression pattern depends on mutant p53 (SW480/OxR), not wild-type p53 (HCT116/OxR). Oxaliplatin-induced LINC00460 in SW480/OxR cells was mainly located in the cytoplasm and was associated with AGO2 protein. LINC00460 functions as a competing endogenous RNA (ceRNA) to promote oxaliplatin resistance through sequestering miR-149-5p/miR-150-5p and upregulating the expression of the microRNA (miRNA) target p53. Knockdown of LINC00460 sensitized SW480/OxR cells to oxaliplatin by modulating p53 and . In turn, mutant p53 positively regulated the expression of LINC00460, thus forming a feedback loop. Clinical data showed that LINC00460 was upregulated in CRC tissues compared with paired normal tissues and was significantly correlated with clinical stage and node (N) status. Our findings uncover a mechanism for the LINC00460-miR-149-5p/miR-150-5p-mutant p53 feedback loop in oxaliplatin resistance of CRC, and they provide potential therapeutic targets for tumor chemoresistance.
奥沙利铂耐药是晚期结直肠癌（CRC）临床治疗中的一个主要挑战。长链非编码RNA（lncRNAs）作为关键调节因子参与肿瘤发生和进展，但其在化疗耐药中的潜在作用尚不清楚。在本研究中，我们报道LINC00460-miR-149-5p/miR-150-5p-突变型p53反馈环与CRC中的奥沙利铂耐药有关。首先，我们发现与亲本奥沙利铂敏感细胞相比，LINC00460在奥沙利铂耐药CRC（CRC/OxR）细胞中表达更高，且这种表达模式依赖于突变型p53（SW480/OxR），而非野生型p53（HCT116/OxR）。奥沙利铂诱导SW480/OxR细胞中的LINC00460主要位于细胞质中，并与AGO2蛋白相关。LINC00460作为一种竞争性内源RNA（ceRNA），通过螯合miR-149-5p/miR-150-5p并上调微小RNA（miRNA）靶标p53的表达来促进奥沙利铂耐药。敲低LINC00460可通过调节p53使SW480/OxR细胞对奥沙利铂敏感。反过来，突变型p53正向调节LINC00460的表达，从而形成一个反馈环。临床数据显示，与配对的正常组织相比，LINC00460在CRC组织中上调，且与临床分期和淋巴结（N）状态显著相关。我们的研究结果揭示了LINC00460-miR-149-5p/miR-150-5p-突变型p53反馈环在CRC奥沙利铂耐药中的机制，并为肿瘤化疗耐药提供了潜在的治疗靶点。
Zotero 插件
