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.

中文翻译：

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CircFOXK2通过与RNA结合蛋白复合并掺入海绵MiR-942促进胰腺导管腺癌的生长和转移。

环状RNA（circRNA）的详细生物学功能在很大程度上尚待探索。使用circRNA测序，我们在胰腺导管腺癌（PDAC）细胞中与非肿瘤人胰导管上皮细胞相比，鉴定出169个差异表达的circRNA。其中，circFOXK2在PDAC细胞和63％的原发性肿瘤中具有明显的上调（84个中的53个）。circFOXK2促进细胞生长，迁移和侵袭，并参与细胞周期进程和凋亡。circFOXK2包含多个miRNA结合位点，充当miR-942的海绵，进而促进ANK1，GDNF和PAX6的表达。一种新颖且高度特异性的circRNA-pulldown，随后进行质谱分析，鉴定出94种circFOXK2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，circFOKX2与YBX1和hnRNPK的相互作用增强了癌基因NUF2和PDXK的表达。敲低circFOXK2可减少YBX1和hnRNPK与NUF2和PDXK的结合，进而降低其表达。总的来说，我们的发现表明，circFOXK2与YBX1和hnRNPK结合可促进致癌蛋白的表达，从而促进PDAC进程。启示：这项研究揭示了circRNA circFOXK2在PDAC进展中的重要作用，表明circFOXK2可能是PDAC的新型诊断标记。我们的发现表明，circFOXK2与YBX1和hnRNPK复合可以促进致癌蛋白的表达，从而促进PDAC的发展。启示：这项研究揭示了circRNA circFOXK2在PDAC进展中的重要作用，表明circFOXK2可能是PDAC的新型诊断标记。我们的发现表明，circFOXK2与YBX1和hnRNPK复合可以促进致癌蛋白的表达，从而促进PDAC的发展。启示：这项研究揭示了circRNA circFOXK2在PDAC进展中的重要作用，表明circFOXK2可能是PDAC的新型诊断标记。