Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China.
Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China; Department of Genetics, School of Life Science, Anhui Medical University, Hefei, Anhui, 230032, China.
Biochem Biophys Res Commun. 2020 Jun 4;526(3):685-691. doi: 10.1016/j.bbrc.2020.03.154. Epub 2020 Apr 3.
Epithelial ovarian cancer (EOC) is one of the most common and lethal gynecological cancers. Novel therapeutic agents have been developed for EOC, but patient survival remains poor. Trastuzumab has been approved for breast and gastric cancers with high expression of human epidermal growth factor receptor 2 (HER2), but it has not achieved any clinical success in EOC. Dysregulated Wnt/β-catenin signaling is involved in cancer development, but whether it plays a role in EOC resistance to trastuzumab remains largely unknown. Here, we observed that high expression of Wnt3a, β-catenin and TCF7L2, which can form a signaling axis in the Wnt/β-catenin pathway, commonly existed in HER2-positive EOC tissue samples and was correlated with a poor patient prognosis. Cell proliferation and migration assays and nude mouse xenograft model experiments demonstrated that the Wnt3a/β-catenin/TCF7L2 signaling axis promoted tumor cell growth and metastasis and reduced tumor sensitivity to trastuzumab. Analysis of downstream Akt signaling suggested that the function of the Wnt3a/β-catenin/TCF7L2 signaling axis was mediated, at least in part, through increasing Akt phosphorylation. Overall, this study reveals a crucial role for the Wnt3a/β-catenin/TCF7L2 signaling axis in EOC resistance to trastuzumab and the potential application of HER2-targeted drugs combined with inhibitors of this signaling axis for EOC treatment.
上皮性卵巢癌 (EOC) 是最常见和最致命的妇科癌症之一。已经开发出了用于 EOC 的新型治疗剂，但患者的生存率仍然很低。曲妥珠单抗已被批准用于人表皮生长因子受体 2 (HER2) 高表达的乳腺癌和胃癌，但在 EOC 中并未取得任何临床成功。Wnt/β-catenin 信号通路的失调参与了癌症的发展，但它是否在 EOC 对曲妥珠单抗的耐药性中起作用在很大程度上仍不清楚。在这里，我们观察到 Wnt3a、β-catenin 和 TCF7L2 的高表达，它们可以在 Wnt/β-catenin 信号通路中形成一个信号轴，在 HER2 阳性的 EOC 组织样本中普遍存在，并与患者预后不良相关。细胞增殖和迁移实验以及裸鼠异种移植模型实验表明，Wnt3a/β-catenin/TCF7L2 信号轴促进肿瘤细胞的生长和转移，并降低肿瘤对曲妥珠单抗的敏感性。对下游 Akt 信号的分析表明，Wnt3a/β-catenin/TCF7L2 信号轴的功能至少部分是通过增加 Akt 磷酸化来介导的。总的来说，这项研究揭示了 Wnt3a/β-catenin/TCF7L2 信号轴在 EOC 对曲妥珠单抗耐药中的关键作用，以及针对该信号轴的 HER2 靶向药物与该信号轴抑制剂联合用于 EOC 治疗的潜在应用。
