LUCAT1 promotes colorectal cancer tumorigenesis by targeting the ribosomal protein L40-MDM2-p53 pathway through binding with UBA52
LUCAT1 promotes colorectal cancer tumorigenesis by targeting the ribosomal protein L40-MDM2-p53 pathway through binding with UBA52
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LUCAT1通过与UBA52结合靶向核糖体蛋白L40-MDM2-p53通路促进结直肠癌肿瘤发生
DOI：
10.1111/cas.13951
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发表时间：
2019-04-01
期刊：
影响因子：
5.7
通讯作者：
Yuan, Xiaoqin
中科院分区：
文献类型：
--
作者：
Zhou, Qianwen;Hou, Zhibo;Yuan, Xiaoqin
结直肠癌（CRC）是美国男性和女性中第三大最常诊断的癌症。然而，驱动CRC肿瘤发生的潜在分子机制仍然不清楚。一些研究已经报道长链非编码RNA（lncRNA）在肿瘤发生中具有重要作用。在此，我们对6对结直肠癌组织及其相应的邻近正常组织进行了转录组微阵列分析。在I/II期和III/IV期CRC组织中检测到总共1705个差异表达的lncRNA（倍数变化大于或等于2或小于或等于0.5）。其中，我们通过对临床数据和癌症基因组图谱的分析，发现lncRNA肺癌相关转录本1（LUCAT 1）在结直肠癌组织中上调，与结直肠癌患者的总体生存率差密切相关。功能研究表明，LUCAT 1在体外和体内促进CRC细胞增殖、凋亡、迁移和侵袭。此外，LUCAT 1的敲低使CRC细胞对奥沙利铂治疗过敏。生物信息学分析表明，LUCAT 1的低表达与p53信号通路有关。染色质分离的RNA纯化，然后质谱和RNA免疫沉淀显示，LUCAT 1结合UBA 52，它编码泛素和60 S核糖体蛋白L40（RPL 40）。我们发现RPL 40在核糖体蛋白-MDM 2-p53通路中起作用，调节p53的表达。总之，我们的研究结果表明，抑制LUCAT 1通过结合UBA 52和激活RPL 40-MDM 2-p53通路诱导CRC细胞周期停滞和凋亡。这些结果暗示LUCAT 1是CRC的潜在预后生物标志物和治疗靶点。
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women in the USA. However, the underlying molecular mechanisms that drive CRC tumorigenesis are still not clear. Several studies have reported that long noncoding RNAs (lncRNAs) have important roles in tumor development. Here, we undertook a transcriptome microarray analysis in 6 pairs of CRC tissues and their corresponding adjacent normal tissues. A total of 1705 differentially expressed lncRNAs were detected in CRC tissues at stages I/II and III/IV (fold change greater than or equal to 2 or less than or equal to 0.5). Among them, we found that the lncRNA lung cancer-associated transcript 1 (LUCAT1) was upregulated in CRC tissues and was closely associated with poor overall survival of CRC patients, through analysis of clinical data and The Cancer Genome Atlas. Functional studies indicated that LUCAT1 promoted CRC cell proliferation, apoptosis, migration, and invasion in vitro and in vivo. Furthermore, knockdown of LUCAT1 rendered CRC cells hypersensitive to oxaliplatin treatment. Mechanistically, bioinformatic analysis indicated that low expression of LUCAT1 was associated with the p53 signaling pathway. Chromatin isolation by RNA purification followed by mass spectrometry and RNA immunoprecipitation revealed that LUCAT1 bound with UBA52, which encodes ubiquitin and 60S ribosomal protein L40 (RPL40). We found that RPL40 functions in the ribosomal protein-MDM2-p53 pathway to regulate p53 expression. Taken together, our findings indicate that suppression of LUCAT1 induces CRC cell cycle arrest and apoptosis by binding UBA52 and activating the RPL40-MDM2-p53 pathway. These results implicate LUCAT1 as a potential prognostic biomarker and therapeutic target for CRC.