CircFOXK2 Promotes Growth and Metastasis of Pancreatic Ductal Adenocarcinoma by Complexing with RNA-Binding Proteins and Sponging MiR-942
CircFOXK2 Promotes Growth and Metastasis of Pancreatic Ductal Adenocarcinoma by Complexing with RNA-Binding Proteins and Sponging MiR-942
复制标题
CircFOXK2 通过与 RNA 结合蛋白复合并海绵化 MiR-942 促进胰腺导管腺癌的生长和转移
DOI：
10.1158/0008-5472.can-19-3268
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发表时间：
2020-06-01
期刊：
影响因子：
11.2
通讯作者：
Chen, Yangchao
中科院分区：
文献类型：
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作者：
Wong, Chi Hin;Lou, Ut Kei;Chen, Yangchao
这项研究揭示了circRNA circFOXK 2在PDAC进展中的重要作用，表明circFOXK 2可能是PDAC的新诊断标志物。环状RNA（circRNA）的详细生物学功能在很大程度上尚未探索。使用circRNA测序，我们确定了169个胰腺导管腺癌（PDAC）细胞与非肿瘤人胰腺导管上皮细胞相比差异表达的circRNA。其中，circFOXK 2在PDAC细胞和63%的原发性肿瘤（84例中的53例）中被证实显著上调。circFOXK 2促进细胞生长、迁移和侵袭，并参与细胞周期进程和凋亡。circFOXK 2含有多个miRNA结合位点，作为miR-942的海绵，进而促进ANK 1、GDNF和PAX 6的表达。一种新的和高度特异性的circRNA-pulldown，随后进行质谱分析，确定了94个circFOXK 2相互作用蛋白，这些蛋白参与细胞粘附，mRNA剪接和结构分子活性。其中，circFOKX 2与YBX 1和hnRNPK的相互作用增强了癌基因NUF 2和PDXK的表达。敲除circFOXK 2减少了YBX 1和hnRNPK与NUF 2和PDXK的结合，从而降低了它们的表达。总的来说，我们的研究结果表明，circFOXK 2与YBX 1和hnRNPK的复合物促进了致癌蛋白的表达，这些蛋白有助于PDAC的进展。重要性：这项研究揭示了circRNA circFOXK 2在PDAC进展中的重要作用，表明circFOXK 2可能是PDAC的新诊断标志物。
This study reveals a prominent role for the circRNA circFOXK2 in PDAC progression, suggesting that circFOXK2 might be a novel diagnostic marker for PDAC. The detailed biological functions of circular RNA (circRNA) are largely unexplored. Using circRNA sequencing, we identified 169 differentially expressed circRNA in pancreatic ductal adenocarcinoma (PDAC) cells compared with nontumor human pancreatic ductal epithelial cells. Among them, circFOXK2 was validated with significant upregulation in PDAC cells and 63% of primary tumors (53 of 84). circFOXK2 promoted cell growth, migration, and invasion and was involved in cell-cycle progression and apoptosis. circFOXK2 contained multiple miRNA binding sites, functioning as a sponge for miR-942, which in turn promoted expression of ANK1, GDNF, and PAX6. A novel and highly specific circRNA-pulldown followed by mass spectrometry analysis identified 94 circFOXK2-interacting proteins, which were involved in cell adhesion, mRNA splicing, and structural molecule activity. Of these, circFOKX2 interactions with YBX1 and hnRNPK enhanced expression of oncogenes NUF2 and PDXK. Knockdown of circFOXK2 reduced binding of YBX1 and hnRNPK to NUF2 and PDXK, in turn decreasing their expression. Collectively, our findings demonstrate that circFOXK2 in complex with YBX1 and hnRNPK promotes expression of oncogenic proteins that contribute to PDAC progression. Significance: This study reveals a prominent role for the circRNA circFOXK2 in PDAC progression, suggesting that circFOXK2 might be a novel diagnostic marker for PDAC.