Pancreatic cancer has poor prognosis and treatment outcomes due to its highly metastatic nature and resistance to current treatments. The RNA-binding protein (RBP) Hu-antigen R (HuR) is a central player in posttranscriptional regulation of cancer-related gene expression, and contributes to tumorigenesis, tumor growth, metastasis, and drug resistance. HuR has been suggested to regulate pancreatic cancer epithelial-to-mesenchymal transition (EMT), but the mechanism was not well understood. Here, we further elucidated the role HuR plays in pancreatic cancer cell EMT, and developed a novel inhibitor specifically interrupting HuR–RNA binding. The data showed that HuR binds to the 3′-UTR of the mRNA of the transcription factor Snail, resulting in stabilization of Snail mRNA and enhanced Snail protein expression, thus promoted EMT, metastasis, and formation of stem-like cancer cells (CSC) in pancreatic cancer cells. siRNA silencing or CRISPR/Cas9 gene deletion of HuR inhibited pancreatic cancer cell EMT, migration, invasion, and inhibited CSCs. HuR knockout cells had dampened tumorigenicity in immunocompromised mice. A novel compound KH-3 interrupted HuR–RNA binding, and KH-3 inhibited pancreatic cancer cell viability, EMT, migration/invasion in vitro. KH-3 showed HuR-dependent activity and inhibited HuR-positive tumor growth and metastasis in vivo.

中文翻译：

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胰腺癌上皮间质转化、转移和癌症干细胞中的 RNA 结合蛋白 Hu 抗原 R

由于胰腺癌的高度转移性和对当前治疗的抵抗力，胰腺癌的预后和治疗结果较差。RNA 结合蛋白 (RBP) Hu 抗原 R (HuR) 是癌症相关基因表达转录后调控的核心参与者，并有助于肿瘤发生、肿瘤生长、转移和耐药性。HuR 已被建议调节胰腺癌上皮间质转化 (EMT)，但其机制尚不清楚。在这里，我们进一步阐明了 HuR 在胰腺癌细胞 EMT 中的作用，并开发了一种新型抑制剂，可特异性中断 HuR-RNA 结合。数据显示，HuR与转录因子Snail mRNA的3'-UTR结合，使Snail mRNA稳定，增强Snail蛋白表达，从而促进EMT、转移、和胰腺癌细胞中干细胞样癌细胞（CSC）的形成。HuR 的 siRNA 沉默或 CRISPR/Cas9 基因缺失可抑制胰腺癌细胞的 EMT、迁移、侵袭，并抑制 CSC。HuR 敲除细胞抑制了免疫功能低下小鼠的致瘤性。一种新的化合物 KH-3 中断了 HuR-RNA 结合，并且 KH-3 在体外抑制了胰腺癌细胞的活力、EMT、迁移/侵袭。KH-3 表现出 HuR 依赖性活性并抑制体内 HuR 阳性肿瘤生长和转移。KH-3 在体外抑制胰腺癌细胞活力、EMT、迁移/侵袭。KH-3 表现出 HuR 依赖性活性并抑制体内 HuR 阳性肿瘤生长和转移。KH-3 在体外抑制胰腺癌细胞活力、EMT、迁移/侵袭。KH-3 表现出 HuR 依赖性活性并抑制体内 HuR 阳性肿瘤生长和转移。