Department of Hepatobiliary Surgery, East Hospital, School of Medicine, Tongji University, Shanghai, China.
Department of Hepatic Surgery, Third Affiliated Hospital of Naval Military Medical University, Shanghai, China.
Gastroenterology. 2023 May;164(6):990-1005. doi: 10.1053/j.gastro.2023.01.041. Epub 2023 Feb 8.
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, but there is a deficiency of early diagnosis biomarkers and therapeutic targets. Drug resistance accounts for most HCC-related deaths, yet the mechanisms underlying drug resistance remain poorly understood.
Expression of Frizzled-10 (FZD10) in liver cancer stem cells (CSCs) was identified by means of RNA sequencing and validated by means of real-time polymerase chain reaction and immunohistochemistry. In vitro and in vivo experiments were used to assess the effect of FZD10 on liver CSC expansion and lenvatinib resistance. RNA sequencing, RNA binding protein immunoprecipitation, and luciferase report assays were applied to explore the mechanism underlying FZD10-mediated liver CSCs expansion and lenvatinib resistance.
Activation of FZD10 in liver CSCs was mediated by METTL3-dependent N6-methyladenosine methylation of FZD10 messenger RNA. Functional studies revealed that FZD10 promotes self-renewal, tumorigenicity, and metastasis of liver CSCs via activating β-catenin and YAP1. The FZD10-β-catenin/YAP1 axis is activated in liver CSCs and predicts poor prognosis. Moreover, FZD10-β-catenin/c-Jun axis transcriptionally activates METTL3 expression, forming a positive feedback loop. Importantly, the FZD10/β-catenin/c-Jun/MEK/ERK axis determines the responses of hepatoma cells to lenvatinib treatment. Analysis of patient cohort, patient-derived tumor organoids, and patient-derived xenografts further suggest that FZD10 might predict lenvatinib clinical benefit in patients with HCC. Furthermore, treatment of lenvatinib-resistant HCC with adeno-associated virus targeting FZD10 or a β-catenin inhibitor restored lenvatinib response.
Elevated FZD10 expression promotes expansion of liver CSCs and lenvatinib resistance, indicating that FZD10 expression is a novel prognostic biomarker and therapeutic target for human HCC.
肝细胞癌（HCC）是全球癌症相关死亡的主要原因之一，但缺乏早期诊断生物标志物和治疗靶点。药物耐药性是导致大多数 HCC 相关死亡的原因，但药物耐药性的机制仍知之甚少。
通过 RNA 测序鉴定肝癌干细胞（CSC）中卷曲蛋白 10（FZD10）的表达，并通过实时聚合酶链反应和免疫组织化学验证。通过体外和体内实验评估 FZD10 对肝 CSC 扩增和仑伐替尼耐药的影响。应用 RNA 测序、RNA 结合蛋白免疫沉淀和荧光素酶报告实验探讨 FZD10 介导肝 CSCs 扩增和仑伐替尼耐药的机制。
METTL3 依赖性 FZD10 信使 RNA 的 N6-甲基腺苷甲基化介导了 FZD10 在肝 CSCs 中的激活。功能研究表明，FZD10 通过激活β-catenin 和 YAP1 促进肝 CSCs 的自我更新、致瘤性和转移。FZD10-β-catenin/YAP1 轴在肝 CSCs 中被激活，并预测预后不良。此外，FZD10-β-catenin/c-Jun 轴转录激活 METTL3 表达，形成正反馈环。重要的是，FZD10/β-catenin/c-Jun/MEK/ERK 轴决定了肝癌细胞对仑伐替尼治疗的反应。对患者队列、患者来源的肿瘤类器官和患者来源的异种移植的分析进一步表明，FZD10 可能预测 HCC 患者对仑伐替尼的临床获益。此外，用靶向 FZD10 的腺相关病毒或β-catenin 抑制剂治疗仑伐替尼耐药的 HCC 恢复了仑伐替尼的反应。
FZD10 表达升高促进肝 CSCs 的扩增和仑伐替尼耐药，表明 FZD10 表达是人类 HCC 的一种新的预后生物标志物和治疗靶点。
