A novel miR-198 replacement therapy for pancreatic cancer

描述（由申请人提供）：我们最近在人胰腺癌（PC）患者样本中发现了通过肿瘤抑制因子microRNA-198连接的致瘤因子相互作用组，并证实了miR-198在PC动物模型中的肿瘤抑制作用。我们发现miR-198在PC中下调，并与间皮素（MSLN）参与一个复杂的相互调控环，MSLN通过NF-κ B介导的同源框转录因子POU 2F 2（OCT-2）诱导抑制miR-198。此外，miR-198抑制导致前B细胞白血病同源框因子1（PBX-1）和含缬沙汀蛋白（VCP）的过表达。PBX-1/VCP轴失调导致致瘤性增加。在PC细胞中重建miR-198通过直接靶向MSLN、PBX-1和VCP导致肿瘤生长减少、转移减少和存活增加。我们的初步数据有力地表明miR-198和这种相互作用组在PC发病机制中的重要作用。此外，我们发现miR-198可以使PC细胞对吉西他滨杀伤敏感，因为miR-198有效地下调PC细胞中的VCP表达并抑制自噬成熟。在这个提议中，我们假设miR-198和这个相互作用组可以作为一个潜在的预后标志物，miR-198替代疗法可以通过一个中心Vantage点攻击这个致瘤网络，并提高临床前动物模型的治疗效果。 提出了三个具体目标：1）。在PC患者样本的大队列中证明miR-198和致瘤因子相互作用组在人PC临床预后中的显著作用; 2）。设计和表征用于将miR-198特异性递送至PC细胞的MSLN特异性靶向miR-198纳米颗粒;和3）。在PC患者来源的异种移植（PDX）小鼠模型中证明靶向MSLN的miR-198替代的治疗功效。该项目将大大有助于PC研究，并将对PC患者的临床实践产生巨大影响。

DESCRIPTION (provided by applicant): We recently discovered a tumorigenic factor interactome connected through the tumor suppressor microRNA-198 in human pancreatic cancer (PC) patient samples and confirmed the tumor suppressive roles of miR-198 in PC animal models. We found that miR-198 is downregulated in PC and is involved in an intricate reciprocal regulatory loop with mesothelin (MSLN), which represses miR-198 through NF-kB-mediated homeobox transcription factor POU2F2 (OCT-2) induction. Furthermore, miR-198 repression leads to overexpression of pre-B-cell leukemia homeobox factor 1 (PBX-1) and valosin-containing protein (VCP). The dysregulated PBX-1/VCP axis leads to an increase in tumorigenicity. Reconstitution of miR-198 in PC cells results in reduced tumor growth, decreased metastasis, and increased survival through direct targeting of MSLN, PBX-1, and VCP. Our preliminary data strongly suggest the significant role of miR-198 and this interactome in PC pathogenesis. In addition, we found that miR-198 can sensitize PC cells for gemcitabine killing because miR-198 effectively downregulates VCP expression and inhibits autophagy maturation in PC cells. In this proposal, we hypothesize that miR-198 and this interactome could serve as a potential prognostic marker and the miR-198 replacement therapy could attack this tumorigenic network through a central vantage point and improve therapeutic efficacy in pre-clinical animal models. Three specific aims are proposed: 1). Demonstrate the significant role of miR-198 and the tumorigenic factor interactome in human PC clinical prognosis in a large cohort of PC patient samples; 2). Design and characterize MSLN-specific targeted miR-198 nanoparticles for specifically delivering miR-198 to PC cells; and 3). Demonstrate the therapeutic efficacy of MSLN-targeted miR-198 replacement in PC patient-derived xenograft (PDX) mouse models. The project will substantially contribute to PC research and will have an enormous impact on clinical practice for patients with PC.