METTL3-m6A-EGFR-axis drives lenvatinib resistance in hepatocellular carcinoma
METTL3-m6A-EGFR-axis drives lenvatinib resistance in hepatocellular carcinoma
复制标题
DOI：
10.1016/j.canlet.2023.216122
复制
发表时间：
2023-03-11
期刊：
影响因子：
9.7
通讯作者：
Xu，Lixia
中科院分区：
文献类型：
--
作者：
Wang，Lina;Yang，Qingxia;Xu，Lixia
Lenvatinib正在成为晚期肝细胞癌（HCC）的一线治疗选择，但耐药仍然是影响其临床长期治疗效果的主要障碍。n6 -甲基腺苷（m6A）是最丰富的mRNA修饰。在此，我们旨在研究m6A在HCC lenvatinib耐药中的调节作用及其潜在机制。我们的数据显示，与亲代细胞相比，HCC lenvatinib耐药（HCC- lr）细胞中的m6A mRNA修饰显著上调。甲基转移酶样3 （Methyltransferase-like 3, METTL3）是m6A调控蛋白中上调幅度最大的蛋白。lenvatinib对原代耐药细胞系MHCC97H和获得性耐药Huh7-LR细胞的METTL3失活对m6A甲基化的遗传或药理学抑制均可降低体外和体内lenvatinib处理后的细胞增殖，增加细胞凋亡。此外，特异性METTL3抑制剂STM2457在多种小鼠HCC模型（包括皮下、原位和流体动力学模型）中改善了肿瘤对lenvatinib的反应。MeRIP-seq结果显示表皮生长因子受体（EGFR）是METTL3的下游靶点。lenvatinib处理HCC-LR细胞后，EGFR过表达消除了METTL3敲低诱导的细胞生长停滞。因此，我们得出结论，使用特异性抑制剂STM2457靶向METTL3可提高体内对lenvatinibin体外和体外的敏感性，表明METTL3可能是克服HCC lenvatinib耐药的潜在治疗靶点。
Lenvatinib is emerging as the first-line therapeutic option for advanced hepatocellular carcinoma (HCC), but drug resistance remains a major hurdle for its long-term therapy efficiency in clinic. N6-methyladenosine (m6A) is the most abundant mRNA modification. Here, we aimed to investigate the modulatory effects and underlying mechanisms of m6A in lenvatinib resistance in HCC. Our data revealed that m6A mRNA modification was significantly upregulated in the HCC lenvatinib resistance (HCC-LR) cells compared to parental cells. Methyltransferase-like 3 (METTL3) was the most significantly upregulated protein among the m6A regulators. Either genetic or pharmacological inhibition of m6A methylation through METTL3 deactivation in primary resistant cell line MHCC97H and acquired resistant Huh7-LR cells decreased cell proliferation and increased cell apoptosis upon lenvatinib treatmentin vitroandin vivo. In addition, the specific METTL3 inhibitor STM2457 improved tumor response to lenvatinib in multiple mouse HCC models, including subcutaneous, orthotopic and hydrodynamic models. The MeRIP-seq results showed that epidermal growth factor receptor (EGFR) was a downstream target of METTL3. EGFR overexpression abrogated the METTL3 knocked down-induced cell growth arrest upon lenvatinib treatment in HCC-LR cells. Thus, we concluded that targeting METTL3 using specific inhibitor STM2457 improved the sensitivity to lenvatinibin vitroandin vivo, indicating that METTL3 may be a potential therapeutic target to overcome lenvatinib resistance in HCC.