Di Fusco Davide, Segreto Maria Teresa, Di Maggio Giulia, Iannucci Andrea, Maresca Claudia, Di Grazia Antonio, Colella Marco, Stolfi Carmine, Monteleone Giovanni, Monteleone Ivan
Department of Systems Medicine, University of "Tor Vergata", 00133 Rome, Italy.
Department of Biomedicine and Prevention, University of "Tor Vergata", 00133 Rome, Italy.
Cancers (Basel). 2023 Oct 13;15(20):4983. doi: 10.3390/cancers15204983.
A number of data indicate that the sources of different kinds of PDAC may be discovered at the transcription/transduction stage. RNA metabolism is manipulated at various steps by different RNA-binding proteins (RBPs), and the deregulation or irregular activity of RBPs is known to contribute to tumor promotion and progression. The insulin-like growth factor 2 mRNA-binding protein family (IMPs), and IMP1 in particular, has been linked with a poor prognosis in PDAC patients; however, little is known about its contribution in PDAC carcinogenesis. In this study, we investigated the function of IMP1 in PDAC. To evaluate IMP1 expression and correlation with PDAC prognosis, we utilized several public databases. Using a specific siRNA IMP1, we analyzed cell death and cell cycle progression in PDAC cell lines and 3D spheroids. The role of IMP1 was also evaluated in vivo in a Panc-1-derived tumor xenograft murine model. Public data suggest that PDAC patients with higher expression of IMP1 showed poor overall and progression-free survival. IMP1 silencing leads to reduced cell growth in PDAC cells and three-dimensional spheroids. Abrogation of IMP1 in PDAC cells showed lower levels of , increased phosphorylation of the cyclin-dependent kinase (CDK)2, and accumulation of PDAC cells in the G1 phase. Immunoprecipitation experiments revealed that IMP1 binds mRNA, thus controlling cell-cycle progression. Ultimately, we proved that suppression of IMP1 blocked in vivo growth of Panc-1 transferred into immunodeficient mice. Our results indicate that IMP1 drives the PDCA cell cycle and represents a novel strategy for overcoming PDCA cell proliferation.
大量数据表明，不同类型的胰腺导管腺癌（PDAC）的来源可能在转录/转导阶段被发现。RNA代谢在不同步骤受到不同RNA结合蛋白（RBPs）的调控，已知RBPs的失调或异常活性会促进肿瘤的发生和发展。胰岛素样生长因子2 mRNA结合蛋白家族（IMPs），尤其是IMP1，与PDAC患者的不良预后有关；然而，其在PDAC致癌过程中的作用却鲜为人知。在本研究中，我们调查了IMP1在PDAC中的功能。为了评估IMP1的表达及其与PDAC预后的相关性，我们利用了几个公共数据库。使用特异性siRNA IMP1，我们分析了PDAC细胞系和三维球体中的细胞死亡和细胞周期进程。IMP1的作用也在源自Panc-1的肿瘤异种移植小鼠模型中进行了体内评估。公共数据表明，IMP1表达较高的PDAC患者总体生存率和无进展生存率较差。IMP1沉默导致PDAC细胞和三维球体中的细胞生长减少。PDAC细胞中IMP1的缺失显示出较低水平的 ，细胞周期蛋白依赖性激酶（CDK）2的磷酸化增加，以及PDAC细胞在G1期的积累。免疫沉淀实验表明，IMP1与 mRNA结合，从而控制细胞周期进程。最终，我们证明抑制IMP1可阻断移植到免疫缺陷小鼠体内的Panc-1的体内生长。我们的结果表明，IMP1驱动PDCA细胞周期，代表了一种克服PDCA细胞增殖的新策略。
