MOE Key Laboratory of Biosystems Homeostasis & Protection, Life Sciences Institute, Zhejiang University, Hangzhou, China.
Shandong Cancer Hospital and Institute, Shandong Cancer Hospital of Shandong First Medical University, Jinan, China.
Hepatology. 2021 Apr;73(4):1381-1398. doi: 10.1002/hep.31448. Epub 2020 Nov 7.
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.
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.
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.
经动脉化疗栓塞术（TACE）是治疗肝细胞癌（HCC）患者的标准局部区域治疗方法，但疗效的总体反应存在差异。我们旨在确定导致 HCC 对 TACE 耐药的关键分子特征和相关途径，以期开发有效的方法来预先选择从 TACE 中获益的患者。
使用了四个包含 680 名患者的独立 HCC 队列。HCC 患者的 microRNA（miRNA）转录组分析显示，有一个与辅助 TACE 后 HCC 复发相关的 41-miRNA 特征，miR-125b 是 HCC 复发患者中下调最明显的 miRNA。一致地，在两个独立的队列中，肿瘤中 miR-125b 表达较低的 HCC 患者在辅助 TACE 后复发的时间明显缩短。在体外和体内，HCC 中 miR-125b 的缺失显着激活了缺氧诱导因子 1α亚基（HIF1α）/pAKT 环。miR-125b 通过与 HIF1A 内部核糖体进入位点区域结合并靶向 YB-1 直接减弱 HIF1α 的翻译，并通过靶向血小板衍生生长因子β（PDGFβ）受体阻断 HIF1α 翻译的自分泌 HIF1α/PDGFβ/pAKT/HIF1α 环。miR-125b 缺失/HIF1α 轴诱导了 CD24 和促红细胞生成素（EPO）的表达，并富集了 TACE 耐药的 CD24 阳性癌症干细胞群体。一致地，HCC 中 CD24 或 EPO 高的患者在辅助 TACE 治疗后预后不良。此外，在 TACE 作为一线治疗的 HCC 患者中，TACE 前血液中高 EPO 也与对 TACE 的反应不良显着相关。
miR-125b 的缺失激活了 HIF1α/pAKT 环，导致 HCC 对 TACE 的耐药性，该轴中的关键节点具有辅助 HCC 患者选择 TACE 治疗的潜力。
