MiR‐125b Loss Activated HIF1α/pAKT Loop, Leading to Trans‐Arterial Chemoembolization Resistance in Hepatocellular Carcinoma

BACKGROUND & AIMS Trans-arterial chemoembolization (TACE) is a standard locoregional therapy for 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 pre-selecting patients with survival benefit from TACE. APPROACH & RESULTS Four independent HCC cohorts with 680 patients were employed. MiRNA transcriptome analysis in HCC patients 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, HCC patients with low miR-125b expression in tumor had significantly shorter time to recurrence upon adjuvant TACE in two independent cohorts. Loss of miR-125b in HCC noticeably activated the HIF1α/pAKT loop in vitro and in vivo. miR-125b directly attenuated HIF1α translation through binding to HIF1A IRES region and targeting YB-1, and blocked an autocrine HIF1α/PDGFβ/pAKT/HIF1α loop of HIF1α translation via targeting PDGFβ receptor. The miR-125b-loss/HIF1α axis induced the expression of CD24 and EPO and enriched a TACE-resistant CD24-positive cancer stem cell population. Consistently, patients with high CD24 or EPO in HCC had poor prognosis upon adjuvant TACE therapy. Additionally, in HCC patients having TACE as their first-line therapy, high EPO in blood prior to TACE was also noticeably related to poor response to TACE. CONCLUSIONS MiR-125b loss activated the HIF1α/pAKT loop, contributing to HCC resistance to TACE and the key nodes in this axis hold the potential in assisting HCC patients to choose TACE therapy.