Mir-125b Loss Activated Hif1 Alpha/Pakt Loop, Leading To Transarterial Chemoembolization Resistance In Hepatocellular Carcinoma

Background and Aims Transarterial chemoembolization (TACE) is a standard locoregional therapy for patients with hepatocellular carcinoma (HCC) patients with a variable overall response in efficacy. We aimed to identify key molecular signatures and related pathways leading to HCC resistance to TACE, with the hope of developing effective approaches in preselecting patients with survival benefit from TACE.Approach and Results Four independent HCC cohorts with 680 patients were used. MicroRNA (miRNA) transcriptome analysis in patients with HCC revealed a 41-miRNA signature related to HCC recurrence after adjuvant TACE, and miR-125b was the top reduced miRNA in patients with HCC recurrence. Consistently, patients with HCC with low miR-125b expression in tumor had significantly shorter time to recurrence following adjuvant TACE in two independent cohorts. Loss of miR-125b in HCC noticeably activated the hypoxia inducible factor 1 alpha subunit (HIF1 alpha)/pAKT loop in vitro and in vivo. miR-125b directly attenuated HIF1 alpha translation through binding to HIF1A internal ribosome entry site region and targeting YB-1, and blocked an autocrine HIF1 alpha/platelet-derived growth factor beta (PDGF beta)/pAKT/HIF1 alpha loop of HIF1 alpha translation by targeting the PDGF beta receptor. The miR-125b-loss/HIF1 alpha axis induced the expression of CD24 and erythropoietin (EPO) and enriched a TACE-resistant CD24-positive cancer stem cell population. Consistently, patients with high CD24 or EPO in HCC had poor prognosis following adjuvant TACE therapy. Additionally, in patients with HCC having TACE as their first-line therapy, high EPO in blood before TACE was also noticeably related to poor response to TACE.Conclusions MiR-125b loss activated the HIF1 alpha/pAKT loop, contributing to HCC resistance to TACE and the key nodes in this axis hold the potential in assisting patients with HCC to choose TACE therapy.