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Published on: September 12, 2019
MiR-125b Loss Activated HIF1α/pAKT Loop, Leading to Transarterial Chemoembolization Resistance in Hepatocellular
Xiyang Wei1, Lei Zhao2, Ruizhe Ren1
1MOE Key Laboratory of Biosystems Homeostasis & Protection, Life Sciences Institute, Zhejiang University, Hangzhou, China.
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 (HIF1α)/pAKT loop in vitro and in vivo. miR-125b directly attenuated HIF1α translation through binding to HIF1A internal ribosome entry site region and targeting YB-1, and blocked an autocrine HIF1α/platelet-derived growth factor β (PDGFβ)/pAKT/HIF1α loop of HIF1α translation by targeting the PDGFβ receptor. The miR-125b-loss/HIF1α 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 HIF1α/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.
Insights
Low miR-125b expression in hepatocellular carcinoma (HCC) promotes TACE resistance by activating the HIF1α/pAKT pathway. Identifying this molecular signature can help select patients who benefit from TACE therapy.
Area of Science:
- Hepatocellular Carcinoma (HCC) Research
- Molecular Oncology
- Cancer Therapeutics
Background:
- Transarterial chemoembolization (TACE) is a standard treatment for HCC, but patient response varies.
- Identifying molecular mechanisms of TACE resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To uncover molecular signatures and pathways driving HCC resistance to TACE.
- To enable preselection of patients who will benefit from TACE therapy.
Main Methods:
- Analysis of miRNA transcriptome in four independent HCC cohorts (680 patients).
- In vitro and in vivo studies to investigate the role of miR-125b and its downstream targets.
- Correlation of molecular markers (CD24, EPO) with TACE response and prognosis.
Main Results:
- A 41-miRNA signature associated with HCC recurrence post-TACE was identified, with miR-125b being significantly reduced.
- Loss of miR-125b activated the HIF1α/pAKT loop, promoting TACE resistance via CD24 and EPO.
- High CD24 or EPO levels in HCC correlated with poor prognosis after TACE; high pre-TACE EPO indicated poor response.
Conclusions:
- MiR-125b loss and subsequent HIF1α/pAKT activation contribute to TACE resistance in HCC.
- Key molecular nodes in this axis can aid in selecting HCC patients for TACE therapy.
