Yuen John G, Hwang Ga-Ram, Fesler Andrew, Intriago Erick, Pal Amartya, Ojha Anushka, Ju Jingfang
bioRxiv. 2023 Aug 15:2023.08.14.553255. doi: 10.1101/2023.08.14.553255.
Pancreatic cancer, including its most common subtype, pancreatic adenocarcinoma (PDAC), has the lowest five-year survival rate among patients with pancreatic cancer in the United States. Despite advancements in anticancer treatment, the overall median survival for patients with PDAC has not dramatically improved. Therefore, there is an urgent need to develop new strategies of treatment to address this issue. Non-coding RNAs, including microRNAs (miRNAs), have been found to have major roles in carcinogenesis and the subsequent treatment of various cancer types like PDAC. In this study, we developed a treatment strategy by modifying tumor suppressor miRNAs, (miR-15a) and (miR-194), with the nucleoside analog chemotherapeutic gemcitabine (Gem) to create Gem-modified mimics of miR-15a (Gem-miR-15a) and miR-194 (Gem-miR-194). 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 alone 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.
Yuen and Hwang have developed a potent therapeutic strategy for patients with pancreatic cancer by modifying microRNAs with gemcitabine.
胰腺癌，包括其最常见的亚型胰腺腺癌（PDAC），在美国胰腺癌患者中的五年生存率最低。尽管抗癌治疗取得了进展，但PDAC患者的总体中位生存期并未显著改善。因此，迫切需要开发新的治疗策略来解决这一问题。已发现非编码RNA，包括微小RNA（miRNA），在致癌作用以及随后对PDAC等各种癌症类型的治疗中起主要作用。在本研究中，我们通过用核苷类似物化疗药物吉西他滨（Gem）修饰肿瘤抑制性miRNA（miR-15a）和（miR-194），开发了一种治疗策略，以创建Gem修饰的miR-15a（Gem-miR-15a）和miR-194（Gem-miR-194）模拟物。在一组PDAC细胞系中，我们发现Gem-miR-15a和Gem-miR-194诱导细胞周期停滞和凋亡，并且这些模拟物是有效的抑制剂，其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，包括Gem-miR-15a的WEE1、CHK1、BMI1和YAP1，以及Gem-miR-194的FOXA1。我们还发现，与单独的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，而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miRNA作为PDAC治疗策略的治疗潜力。
Yuen和Hwang通过用吉西他滨修饰微小RNA，为胰腺癌患者开发了一种有效的治疗策略。
