2. Academic Validation
  3. M6A-mediated upregulation of FZD10 regulates liver cancer stem cells properties and lenvatinib resistance through WNT/β-catenin and Hippo signaling pathways

M6A-mediated upregulation of FZD10 regulates liver cancer stem cells properties and lenvatinib resistance through WNT/β-catenin and Hippo signaling pathways

  • Gastroenterology. 2023 Feb 8;S0016-5085(23)00114-2. doi: 10.1053/j.gastro.2023.01.041.
Jinghan Wang 1,  Hongming Yu 2,  Wei Dong 3,  Cheng Zhang 4,  Mingtai Hu 1,  Wencong Ma 1,  Xiaoqing Jiang 5,  Hengyu Li 6,  Pinghua Yang 7,  Daimin Xiang 8
Affiliations

Affiliations

  • 1 Department of hepatobiliary surgery, East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
  • 2 Department of Hepatic Surgery, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China.
  • 3 Department of Pathology, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China.
  • 4 Department of Gastroenterology, Bethune International Peace Hospital, Shijiazhuang, Hebei, China.
  • 5 Department of Hepatic Surgery, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China. Electronic address: jxqehbh@sina.com.
  • 6 Department of Breast and Thyroid Surgery, Changhai Hospital, Naval Military Medical University, Shanghai 200433, China. Electronic address: lhy@smmu.edu.cn.
  • 7 Department of Hepatic Surgery, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China. Electronic address: yangpinghua2008@163.com.
  • 8 Department of hepatobiliary surgery, East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. Electronic address: xdm20079@126.com.
PMID: 36764493 DOI: 10.1053/j.gastro.2023.01.041
Abstract

Background & aims: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, but there is deficiency of early diagnosis biomarkers and therapeutic targets. Drug-resistance account for most HCC-related deaths, yet the mechanisms underlying drug-resistance remain poorly understood.

Methods: The expression of Frizzled-10 (FZD10) in liver Cancer Stem Cells (CSCs) was identified by RNA sequencing and validated by Real-Time PCR and immunohistochemistry. In vitro and in vivo experiments were used to assess the effect of FZD10 on liver CSCs 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.

Results: The activation of FZD10 in liver CSCs was mediated by METTL3-dependent m6A methylation of FZD10 mRNA. Functional studies revealed that FZD10 promotes liver CSCs self-renewal, tumorigenicity and metastasis 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, 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 (PDOs) and patient-derived xenografts (PDXs) further suggest that FZD10 might predict lenvatinib clinical benefit in HCC patients. Furthermore, treatment of lenvatinib-resistant HCC with adeno-associated virus (AAV) targeting FZD10 or an β-catenin Inhibitor restored lenvatinib response.

Conclusions: Elevated FZD10 expression promotes liver CSCs expansion and lenvatinib resistance, indicating that FZD10 expression is a novel prognostic biomarker and therapeutic target for human HCC.

Keywords

Cancer stem cells; FZD10; Hepatocellular carcinoma; Lenvatinib; m6A.

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