HnRNPK/miR-223/FBXW7 feedback cascade promotes pancreatic cancer cell growth and invasion.
HnRNPK/miR-223/FBXW7 feedback cascade promotes pancreatic cancer cell growth and invasion.
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DOI：
10.18632/oncotarget.15529
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发表时间：
2017-03-21
期刊：
影响因子：
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通讯作者：
Zhang Z
中科院分区：
文献类型：
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作者：
He D;Huang C;Zhou Q;Liu D;Xiong L;Xiang H;Ma G;Zhang Z
多项研究已发现 miR-223 与多种类型的癌症密切相关，包括胰腺导管腺癌 (PDAC)。然而，其在 PDAC 中的作用和调节机制仍不清楚。在这项研究中，我们发现 PDAC 临床样本中 miR-223 的表达水平升高（81.6%）。 miR-223 的上调可增加 PDAC 细胞在体外和体内的增殖、迁移和侵袭能力。从机制上讲，miR-223 直接靶向 FBXW7，并且 FBXW7 的过表达可恢复 miR-223 诱导的 PDAC 细胞的急剧增殖。有趣的是，发现 miR-223 启动子与 hnRNPK 形成共沉淀复合物，并且 PDAC 细胞中 hnRNPK 的 siRNA 敲低降低了 miR-223 的水平。这些结果表明 hnRNPK 是一种细胞蛋白，可结合并影响 PDAC 中 miR-223 的积累。此外，FBXW7 与 hnRNPK 相互作用并促进其降解，这需要 GSK3 在苏氨酸 1695 处磷酸化 hnRNPK。一致地，我们观察到 FBXW7 和 miR-223 之间的反向表达模式，而在人 PDAC 组织中发现 miR-223 和 hnRNPK 之间的正表达模式。这些数据揭示了人类 PDAC 中重要的新 miR-223/FBXW7/HnRNPK 反馈级联。
Several studies have identified miR-223 critically involved in various types of cancer, including pancreatic ductal adenocarcinoma (PDAC). However, its action and regulatory mechanisms in PDAC remains largely unclear. In this study, we found that the expression levels of miR-223 were increased in clinical samples with PDAC (81.6%). The upregulation of miR-223 increases the proliferation, migration, and invasive abilities of PDAC cells in vitro and in vivo. Mechanistically, miR-223 directly targeted FBXW7 and overexpression of FBXW7 reverted miR-223- induced drastic proliferation in PDAC cells. Interestingly, miR-223 promoter was found to form a coprecipitable complex with hnRNPK, and siRNA knockdown of hnRNPK in PDAC cells reduced the levels of miR-223. These results show that hnRNPK is a cellular protein that binds and affects the accumulation of miR-223 in PDAC. Furthermore, FBXW7 interacts with hnRNPK and promotes its degradation, which requires phosphorylation of hnRNPK at threonine 1695 by GSK3. Consistently, we observed an inverse expression pattern between FBXW7 and miR-223, whereas a positive expression pattern between miR-223 and hnRNPK was found in human PDAC tissues. These data unveiled an important new miR-223/FBXW7/HnRNPK feedback cascade in human PDAC.