Marin-Muller Christian, Li Dali, Lü Jian-Ming, Liang Zhengdong, Vega-Martínez Osvaldo, Crawford Sue E, Estes Mary K, Fisher William E, Chen Changyi, Yao Qizhi
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
Pharmaceutics. 2023 Jul 28;15(8):2038. doi: 10.3390/pharmaceutics15082038.
Pancreatic ductal adenocarcinoma (PDAC) remains an extremely aggressive disease characterized by rapidly acquired multi-drug resistance, including to first-line chemotherapeutic agent gemcitabine. Autophagy is a process that is often exploited by cancer and is one of several intrinsic factors associated with resistance to gemcitabine. We have previously found that miR-198 acts as a tumor suppressor in PDAC through the targeting of factors including Valosin-containing protein (VCP). VCP has been reported to play an important role in autophagic flux. In this study, we investigated whether the repression of VCP through miR-198 administration disrupts the autophagy process and sensitizes PDAC cells to gemcitabine treatment in vitro. Moreover, we used LGA-PEI (LPNP) nanoparticles to effectively administer miR-198 to tumors in vivo, inducing tumor sensitization to gemcitabine and leading to a significant reduction in tumor burden and metastases and a concomitant downregulation of VCP expression and autophagy maturation. Our results indicate a potential therapeutic strategy for targeting gemcitabine resistant PDAC and establishes the use of LPNPs for effective therapeutic delivery of nucleic acids in vitro and in vivo.
胰腺导管腺癌（PDAC）仍然是一种极具侵袭性的疾病，其特征是迅速获得多药耐药性，包括对一线化疗药物吉西他滨的耐药。自噬是一种常被癌症利用的过程，是与吉西他滨耐药相关的几个内在因素之一。我们之前发现，miR-198通过靶向包括含缬酪肽蛋白（VCP）在内的因子，在PDAC中发挥肿瘤抑制作用。据报道，VCP在自噬通量中起重要作用。在本研究中，我们调查了通过给予miR-198抑制VCP是否会破坏自噬过程，并使PDAC细胞在体外对吉西他滨治疗敏感。此外，我们使用LGA-PEI（LPNP）纳米颗粒在体内有效地将miR-198递送至肿瘤，诱导肿瘤对吉西他滨敏感，并导致肿瘤负荷和转移显著减少，同时下调VCP表达和自噬成熟。我们的结果表明了一种针对吉西他滨耐药性PDAC的潜在治疗策略，并确立了LPNP在体外和体内有效治疗性递送核酸的用途。
