Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Medicine, Shandong University, Shandong, P. R. China.
Department of Pathology, Weifang Medical University, Shandong, P. R. China.
Oncogene. 2019 Nov;38(45):7073-7088. doi: 10.1038/s41388-019-0934-z. Epub 2019 Aug 13.
Long non-coding RNAs (lncRNAs) have emerged as critical regulators in gastric cancer (GC). LncRNA expression microarray data indicate that KRT19P3 (Keratin 19 Pseudogene 3) is downregulated in GC samples. However, the expression pattern and molecular mechanism of KRT19P3 in GC have not been characterized. The present study confirmed the downregulation of KRT19P3 in GC tissues and cells. Decreased expression of KRT19P3 was correlated with larger tumor size, advanced TNM stage, Lauren's classification, positive lymph node metastasis, and poor prognosis. Enforced expression of KRT19P3 significantly inhibited cell proliferation, migration, and invasion in vitro, as well as tumorigenesis and metastasis in vivo. Conversely, KRT19P3 knockdown had opposite effects. Mechanistically, RNA pull-down and RNA immunoprecipitation assay revealed that KRT19P3 could directly bind COPS7A. KRT19P3 enhanced COPS7A protein stability in GC cells, and KRT19P3 suppressed GC cell proliferation and metastasis partly through regulation of COPS7A expression. COPS7A could promote deubiquitinylation of IκBα, which was executed by CSN-associated deubiquitinylase USP15, and then KRT19P3 inactivated nuclear factor kappa-B (NF-κB) signaling pathway in a COPS7A-dependent manner. For the first time, we revealed that KRT19P3 could suppress tumor growth and metastasis through COPS7A-mediated NF-κB pathway, which may serve as potential targets for treatment of GC in the future.
长链非编码 RNA（lncRNA）已成为胃癌（GC）的关键调控因子。lncRNA 表达微阵列数据表明，KRT19P3（角蛋白 19 假基因 3）在 GC 样本中下调。然而，KRT19P3 在 GC 中的表达模式和分子机制尚未得到表征。本研究证实了 KRT19P3 在 GC 组织和细胞中的下调。KRT19P3 的表达下调与肿瘤体积较大、TNM 分期较晚、Lauren 分类、阳性淋巴结转移和预后不良相关。KRT19P3 的过表达显著抑制了体外细胞增殖、迁移和侵袭，以及体内肿瘤发生和转移。相反，KRT19P3 的敲低则产生相反的效果。机制上，RNA 下拉和 RNA 免疫沉淀实验表明，KRT19P3 可以直接与 COPS7A 结合。KRT19P3 在 GC 细胞中增强了 COPS7A 蛋白的稳定性，并且 KRT19P3 通过调节 COPS7A 表达部分抑制了 GC 细胞的增殖和转移。COPS7A 可以促进 IκBα 的去泛素化，这是由 CSN 相关的去泛素化酶 USP15 执行的，然后 KRT19P3 以 COPS7A 依赖的方式使核因子 kappa-B（NF-κB）信号通路失活。我们首次揭示，KRT19P3 可以通过 COPS7A 介导的 NF-κB 通路抑制肿瘤生长和转移，这可能成为未来治疗 GC 的潜在靶点。
