Wang Yu, Jiang Rongke, Wang Qiang, Li Yanfang, Sun Ziqian, Zhao Hongying
Department of General Surgery, Xuzhou Cancer Hospital, Xuzhou 221000, China.
Department of Hematology and Oncology, Xuzhou Cancer Hospital, Xuzhou 221000, China.
Mol Ther Nucleic Acids. 2021 Jan 26;24:832-844. doi: 10.1016/j.omtn.2021.01.025. eCollection 2021 Jun 4.
Gastric cancer remains one of the most dangerous cancers, bringing suffering and economic burden to people worldwide. Long noncoding RNAs (lncRNAs) exhibit great potentials for targeted therapy of various cancers. In this investigation, we tested mechanisms by which LINC01021 may regulate gastric cancer progression. We collected gastric cancer tissues and procured cell lines to explore the potential factors by which LINC01021 had effects on angiogenesis, invasion, and migration, by quantitative reverse-transcription polymerase chain reaction (qRT-PCR), Transwell assay, and western blot analysis. Relationships among LINC01021, Caudal-type homeobox 2 (CDX2), and KISS1 were validated by dual-luciferase gene reporter, RNA pull-down, and RNA immunoprecipitation assays. Additionally, a murine model was developed to further explore the impact of LINC01021 on tumors in vivo. LINC01021 was upregulated in gastric cancer tissues and cells. LINC01021 regulated KISS1 through CDK2, which promoted phosphorylation and nuclear export in CDX2. Inhibition of LINC01021 suppressed the tumorigenesis of gastric cancer. Further, silencing LINC01021 exerted an inhibitory effect on cancer cell migration, invasion, and angiogenesis by promoting the binding between CDX2 and KISS1, while inhibiting that between CDK2 and CDX2. Taken altogether, high LINC01021 expression in gastric cancer promotes malignant cell migration and angiogenesis by downregulation of KISS1 through CDK2-mediated CDX2 phosphorylation.
胃癌仍然是最危险的癌症之一，给全世界的人们带来痛苦和经济负担。长链非编码RNA（lncRNA）在各种癌症的靶向治疗中显示出巨大潜力。在本研究中，我们测试了LINC01021可能调控胃癌进展的机制。我们收集了胃癌组织并获取了细胞系，通过定量逆转录聚合酶链反应（qRT-PCR）、Transwell实验和蛋白质印迹分析，探索LINC01021影响血管生成、侵袭和迁移的潜在因素。通过双荧光素酶基因报告实验、RNA下拉实验和RNA免疫沉淀实验验证了LINC01021、尾型同源盒2（CDX2）和KISS1之间的关系。此外，建立了小鼠模型以进一步探索LINC01021在体内对肿瘤的影响。LINC01021在胃癌组织和细胞中上调。LINC01021通过细胞周期蛋白依赖性激酶2（CDK2）调控KISS1，这促进了CDX2的磷酸化和核输出。抑制LINC01021可抑制胃癌的肿瘤发生。此外，沉默LINC01021通过促进CDX2与KISS1之间的结合，同时抑制CDK2与CDX2之间的结合，对癌细胞的迁移、侵袭和血管生成产生抑制作用。综上所述，胃癌中LINC01021的高表达通过CDK2介导的CDX2磷酸化下调KISS1，促进恶性细胞迁移和血管生成。
