结直肠癌(CRC)以其高发病率和高死亡率居于恶性肿瘤的前列。5-氟尿嘧啶(5-FU)是治疗CRC最广泛使用的有效药物之一。然而,迫切需要减少其全身副作用和化学耐药性,为了使基于5-FU的化疗在CRC的治疗中更有效。在这项研究中,建立工程化的CRC细胞以过度表达miR-323a-3p,它是一种靶向EGFR和TYMS的肿瘤抑制剂。然后用合适的收集和纯化方法获得装载miR-323a-3p的外来体(miR-Exo)。我们发现miR-Exo通过直接靶向EGFR的方式显著抑制CRC细胞增殖并诱导细胞凋亡,这最终导致在细胞衍生的异种移植物(CDX)和患者衍生的异种移植物(PDX)肿瘤小鼠模型中期望的肿瘤消退。此外,我们发现从miR-Exo释放的miR-323a-3p直接抑制CRC细胞中5-FU抗性诱导的胸苷酸合成酶(TYMS)的上调,导致5-FU的肿瘤细胞毒性恢复。MiR-Exo可通过靶向EGFR和TYMS有效诱导CRC细胞凋亡,并增强5-FU对CRC的治疗作用。我们的工作证明了miR-Exo用于晚期CRC生物治疗的效力。
Colorectal cancer (CRC) is in the forefront of malignancies for its high incidence and mortality. 5-Fluorouracil (5-FU) is one of the most widely used effective drugs for the treatment of CRC. However, there is an urgent need in reducing its systemic side effects and chemoresistance, in order to make 5-FU-based chemotherapy more effective in the treatment of CRC. In this study, engineered CRC cells were established to overexpress miR-323a-3p, which was a tumor suppressor that targeted both EGFR and TYMS. Then miR-323a-3p-loaded exosomes (miR-Exo) were obtained with suitable methods of collection and purification. We found that miR-Exo significantly inhibited CRC cell proliferation and induced apoptosis by the way of targeting EGFR directly in the cells, which eventually led to desirable tumor regression in the cell derived xenograft (CDX) and patient derived xenograft (PDX) tumor mice models. Moreover, we discovered that miR-323a-3p released from miR-Exo directly inhibited the upregulation of thymidylate synthase (TYMS) induced by 5-FU-resistence in CRC cells, resulting in the revival of tumor cytotoxicity from 5-FU. MiR-Exo could effectively induce the CRC cell apoptosis by targeting EGFR and TYMS, and enhance the therapeutic effects of 5-FU on CRC. Our work demonstrates the potency of miR-Exo for advanced CRC biotherapy.