The Wnt3a/β-catenin/TCF7L2 signaling axis reduces the sensitivity of HER2-positive epithelial ovarian cancer to trastuzumab.

Apr 7, 2020

Contributor: Guodong Shen,Qian Gao,Fenfen Liu,Yan Zhang,Meng Dai,Tingting Zhao,Min Cheng,Tingjuan Xu,Peipei Jin,Wu Yin,Dabing Huang,Haiyan Weng,Wen Chen,Huirong Ren,Xuanxuan Mu,Xinchun Wu,Shilian Hu

The Wnt3a/β-catenin/TCF7L2 signaling axis reduces the sensitivity of HER2-positive epithelial ovarian cancer to trastuzumab.

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.
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

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About The Expert

Guodong Shen

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. Electronic address: gdshen@ustc.edu.cn.

Qian Gao

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.

Fenfen Liu

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.

Yan Zhang

Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China; School of Health Services Management, Anhui Medical University, Hefei, Anhui, 230032, China.

Meng Dai

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.

Tingting Zhao

Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China; Department of Gynecology and Obstetrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.

Min Cheng

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.

Tingjuan Xu

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.

Peipei Jin

Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China.

Wu Yin

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.

Dabing Huang

Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China; Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.

Haiyan Weng

Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.

Wen Chen

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.

Huirong Ren

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.

Xuanxuan Mu

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.

Xinchun Wu

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.

Shilian Hu

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. Electronic address: hushilian@126.com.

References

PubMed