G-LERP/miR-374i-b Attenuates IRI and Suppresses Hepatocellular Carcinoma Progression.

[BACKGROUND] Liver transplantation (LT) is the most effective therapeutic strategy for late-stage hepatocellular carcinoma (HCC), but it is prone to ischemia-reperfusion injury (IRI), leading to poor prognosis. Previous articles have reported that miR-374b-5p expression is increased in HCC tissues, and its relationship with IRI and HCC carcinoma progression is unclear.

[METHODS] Previous reports have shown that miR-374b-5p expression is significantly upregulated in HCC tissues. The effect of miR-374b-5p on patient symptoms and prognosis were analyzed from The Cancer Genome Atlas database and liver specimens from LT patients. To further explore its therapeutic potential, a liver-targeted esterase-responsive gene delivery system (G-LERP/miR-374i-b) was developed to downregulate miR-374b-5p expression in the mouse hepatic IRI (HIRI) model. An orthotopic HCC model was further established to mimic the postoperative recurrence of HCC.

[RESULTS] In this study, we found that miR-374b-5p expression correlates with tumor size and microvascular invasion based on patients' clinical information. Patients with low miR-374b-5p expression had a higher Milan criteria score and a lower Model for End-stage Liver Disease score. We verified the positive correlation between miR-374b-5p expression and the proliferation and invasion of HCC cells. Effective downregulation of miR-374b-5p simultaneously alleviated HIRI and reduced tumor burden by 56%, whereas miR-374b-5p upregulation promoted HCC progression. Furthermore, we found G-LERP/miR-374i-b attenuated hepatic inflammation by downregulating the nuclear factor kappa-B pathway, thereby reducing HIRI and the risk of HCC recurrence.

[CONCLUSIONS] This research is the first to demonstrate miR-374b-5p as a dual therapeutic target during LT and postoperative recurrence of HCC. Preintervention of miR-374b-5p using an esterase-responsive gene delivery system during the preoperative period simultaneously alleviates IRI and suppresses HCC progression.