Yuen John G, Hwang Ga-Ram, Fesler Andrew, Intriago Erick, Pal Amartya, Ojha Anushka, Ju Jingfang
Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Medical Scientist Training Program, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Mol Ther Oncol. 2024 Jan 26;32(1):200769. doi: 10.1016/j.omton.2024.200769. eCollection 2024 Mar 21.
Despite the recent advancement in diagnosis and therapy, pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is still the most lethal cancer with a low five-year survival rate. There is an urgent need to develop new therapies to address this issue. In this study, we developed a treatment strategy by modifying tumor suppressor miRNAs, miR-15a and miR-194, with the chemotherapeutic gemcitabine (Gem) to create Gem-modified mimics, Gem-miR-15a and Gem-miR-194, respectively. In a panel of PDAC cell lines, we found that Gem-miR-15a and Gem-miR-194 induce cell-cycle arrest and apoptosis, and these mimics are potent inhibitors with IC values up to several hundred fold less than their native counterparts or Gem alone. Furthermore, we found that Gem-miR-15a and Gem-miR-194 retained miRNA function by downregulating the expression of several key targets including WEE1, CHK1, BMI1, and YAP1 for Gem-miR-15a, and FOXA1 for Gem-miR-194. We also found that our Gem-modified miRNA mimics exhibit an enhanced efficacy compared to Gem in patient-derived PDAC organoids. Furthermore, we observed that Gem-miR-15a significantly inhibits PDAC tumor growth without observing any noticeable signs of toxicity. Overall, our results demonstrate the therapeutic potential of Gem-modified miRNAs as a treatment strategy for PDAC.
尽管近期在诊断和治疗方面取得了进展，但胰腺导管腺癌（PDAC）作为最常见的胰腺癌类型，仍然是致死率最高的癌症，五年生存率很低。迫切需要开发新的治疗方法来解决这一问题。在本研究中，我们通过用化疗药物吉西他滨（Gem）修饰肿瘤抑制性 microRNA（miRNA）——miR-15a 和 miR-194，分别制备了 Gem 修饰的模拟物 Gem-miR-15a 和 Gem-miR-194，从而制定了一种治疗策略。在一组 PDAC 细胞系中，我们发现 Gem-miR-15a 和 Gem-miR-194 可诱导细胞周期停滞和凋亡，并且这些模拟物是强效抑制剂，其半数抑制浓度（IC）值比其天然对应物或单独的 Gem 低数百倍。此外，我们发现 Gem-miR-15a 和 Gem-miR-194 通过下调几个关键靶点的表达来保留 miRNA 功能，对于 Gem-miR-15a 来说，这些靶点包括 WEE1、CHK1、BMI1 和 YAP1，对于 Gem-miR-194 来说是 FOXA1。我们还发现，与 Gem 相比，我们的 Gem 修饰的 miRNA 模拟物在患者来源的 PDAC 类器官中表现出增强的疗效。此外，我们观察到 Gem-miR-15a 显著抑制 PDAC 肿瘤生长，且未观察到任何明显的毒性迹象。总体而言，我们的结果证明了 Gem 修饰的 miRNAs 作为 PDAC 治疗策略的治疗潜力。
