lncRNA MEF和c-Myc的相互调控驱动结直肠癌肿瘤发生

IF 4.8 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Neoplasia Pub Date : 2024-02-01 DOI:10.1016/j.neo.2024.100971
Shuang Wu , Xiangyu Dai , Zhipu Zhu , Dianhui Fan , Su Jiang , Yi Dong , Bing Chen , Qi Xie , Zhihui Yao , Qun Li , Rick Francis Thorne , Yao Lu , Hao Gu , Wanglai Hu
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引用次数: 0

摘要

半数以上的癌症都显示出 c-Myc 的异常表达,因此 c-Myc 可以说是人类最重要的致癌基因。失调的长非编码 RNA(lncRNA)通常也与肿瘤发生有关,而且已经有一些有限的例子表明,lncRNA 是 c-Myc 表达和活性的生物调节因子。在这里,我们证明了名为c-Myc增强因子(MEF)的lncRNA与c-Myc之间的合作关系,它既是c-Myc的转录靶标,也是c-Myc表达的驱动因子。从机制上讲,MEF通过与结直肠癌细胞中的hnRNPK结合并稳定其表达发挥作用。MEF 与 hnRNPK 的相互作用会破坏 hnRNPK 与 E3 泛素连接酶 TRIM25 之间的结合,从而减弱 TRIM25 依赖的 hnRNPK 泛素化和蛋白酶体破坏。反过来,通过 MEF 稳定 hnRNPK 会增强 c-Myc 的翻译,从而提高 c-Myc 的表达。此外,在 shRNA 介导的基因敲除和过表达研究中,通过调节 MEF 的表达发现,MEF 的表达对结直肠癌细胞的体外和体内增殖和存活至关重要。从临床角度来看,我们发现与邻近正常组织相比,MEF 在结直肠癌组织中的表达有不同程度的增加。此外,MEF、c-Myc 和 hnRNPK 之间存在相关性,这表明 MEF-c-Myc 正反馈环在患者体内非常活跃。这些数据共同证明了 MEF 是 c-Myc 网络的关键伙伴,并建议将 MEF 作为结直肠癌的重要治疗靶点。
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Reciprocal regulation of lncRNA MEF and c-Myc drives colorectal cancer tumorigenesis

More than half of all cancers demonstrate aberrant c-Myc expression, making this arguably the most important human oncogene. Deregulated long non-coding RNAs (lncRNAs) are also commonly implicated in tumorigenesis, and some limited examples have been established where lncRNAs act as biological tuners of c-Myc expression and activity. Here, we demonstrate that the lncRNA denoted c-Myc Enhancing Factor (MEF) enjoys a cooperative relationship with c-Myc, both as a transcriptional target and driver of c-Myc expression. Mechanistically, MEF functions by binding to and stabilizing the expression of hnRNPK in colorectal cancer cells. The MEF-hnRNPK interaction serves to disrupt binding between hnRNPK and the E3 ubiquitin ligase TRIM25, which attenuates TRIM25-dependent hnRNPK ubiquitination and proteasomal destruction. In turn, the stabilization of hnRNPK through MEF enhances c-Myc expression by augmenting the translation c-Myc. Moreover, modulating the expression of MEF in shRNA-mediated knockdown and overexpression studies revealed that MEF expression is essential for colorectal cancer cell proliferation and survival, both in vitro and in vivo. From the clinical perspective, we show that MEF expression is differentially increased in colorectal cancer tissues compared to normal adjacent tissues. Further, correlations exist between MEF, c-Myc, and hnRNPK suggesting the MEF-c-Myc positive feedback loop is active in patients. Together these data demonstrate that MEF is a pivotal partner of the c-Myc network and propose MEF as a valuable therapeutic target for colorectal cancer.

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来源期刊
Neoplasia
Neoplasia 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
82
审稿时长
26 days
期刊介绍: Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.
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