Long noncoding RNA PiHL regulates p53 protein stability through GRWD1/RPL11/MDM2 axis in colorectal cancer
Long noncoding RNA PiHL regulates p53 protein stability through GRWD1/RPL11/MDM2 axis in colorectal cancer
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DOI：
10.7150/thno.36045
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Guan, Ming
中科院分区：
文献类型：
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作者：
Deng, Xuan;Li, Sihan;Guan, Ming
我们发现了一种新的长链非编码RNA（lncRNA）在结直肠癌（CRC）中上调。方法：利用TCGA数据库筛选LncRNA候选基因，并对其在结直肠癌发生中的作用及临床意义进行研究。通过qRT-PCR和微阵列研究配对肿瘤和正常组织中的LncRNA表达谱。通过多变量考克斯回归分析评估签名在生存预测中的独立性。结果：在大肠癌8q24.21中发现了一个新的长非编码基因PiHL（P53 inHibiting LncRNA），它是p53负调控基因。PiHL在CRC中显著上调，并且是CRC不良预后的独立预测因子。进一步的体外和体内模型表明，PiHL是至关重要的，在维持细胞增殖和诱导5-FU化疗耐药，通过p53依赖性的方式。从机制上讲，PiHL通过增强GRWD 1和RPL 11复合物的形成，将RPL 11与MDM 2隔离，从而促进p53泛素化。结论：我们的研究阐明了癌细胞如何劫持PiHL-p53轴以促进CRC进展和化疗耐药。PiHL在结直肠癌的发生中起致癌作用，是一个独立的预后因素，也是结直肠癌患者的潜在治疗靶点。
We identified a novel long noncoding RNA (lncRNA) upregulated in colorectal cancer (CRC). We elucidated its role and clinical significance in CRC carcinogenesis.Methods: LncRNA candidates were identified using TCGA database. LncRNA expression profiles were studied by qRT-PCR and microarray in paired tumor and normal tissues. The independence of the signature in survival prediction was evaluated by multivariable Cox regression analysis. The mechanisms of lncRNA function and regulation in CRC were examined using molecular biological methods.Results: We identified a novel long noncoding gene (PiHL, P53 inHibiting LncRNA) from 8q24.21 as a p53 negative regulator. PiHL is drastically upregulated in CRC and is an independent predictor of CRC poor prognosis. Further in vitro and in vivo models demonstrated that PiHL was crucial in maintaining cell proliferation and inducing 5-FU chemoresistance through a p53-dependent manner. Mechanistically, PiHL acts to promote p53 ubiquitination by sequestering RPL11 from MDM2, through enhancing GRWD1 and RPL11 complex formation. We further show that p53 can directly bind to PiHL promoter and regulating its expression.Conclusion: Our study illustrates how cancer cells hijack the PiHL-p53 axis to promote CRC progression and chemoresistance. PiHL plays an oncogenic role in CRC carcinogenesis and is an independent prognostic factor as well as a potential therapeutic target for CRC patients.