Ding Jie, Zhao Jingjing, Huan Lin, Liu Yizhe, Qiao Yejun, Wang Zhen, Chen Zhiao, Huang Shenglin, Zhao Yingjun, He Xianghuo
Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
Hepatology. 2020 Nov;72(5):1666-1681. doi: 10.1002/hep.31195. Epub 2020 Oct 19.
The nuclear factor kappa B (NF-κB) signaling pathway is important for linking inflammation and tumorigenesis. Here, we characterized an NF-κB signaling activation-induced long intergenic noncoding (LINC) RNA in hepatocellular carcinoma (HCC), LINC00665, that contributes to the enhanced cell proliferation of HCC cells both in vitro and in vivo.
LINC00665 physically interacts with the double-stranded RNA (dsRNA)-activated protein kinase (PKR), enhances its activation, and maintains its protein stability by blocking ubiquitin/proteasome-dependent degradation, resulting in a positive feedback regulation of NF-κB signaling in HCC cells. Notably, patients with HCC and higher LINC00665 have poorer outcomes in the clinic.
Our findings indicate that LINC00665 is involved in the NF-κB signaling activation in HCC cells and that the inflammatory LINC00665/PKR/NF-κB loop plays important oncogenic roles in hepatic cancer progression and may be a potential therapeutic target.
核因子κB（NF-κB）信号通路对于连接炎症与肿瘤发生至关重要。在此，我们鉴定了一种在肝细胞癌（HCC）中由NF-κB信号激活诱导的长链基因间非编码（LINC）RNA，即LINC00665，其在体外和体内均有助于增强HCC细胞的增殖。
LINC00665与双链RNA（dsRNA）激活蛋白激酶（PKR）发生物理相互作用，增强其激活，并通过阻断泛素/蛋白酶体依赖性降解来维持其蛋白质稳定性，从而导致HCC细胞中NF-κB信号的正反馈调节。值得注意的是，HCC患者中LINC00665水平较高者在临床上预后较差。
我们的研究结果表明，LINC00665参与HCC细胞中的NF-κB信号激活，并且炎症性的LINC00665/PKR/NF-κB环路在肝癌进展中发挥重要的致癌作用，可能是一个潜在的治疗靶点。
