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

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

doi:10.1016/j.bbrc.2020.03.154

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

Biochem Biophys Res Commun. 2020 Jun 4;526(3):685-691. doi: 10.1016/j.bbrc.2020.03.154. Epub 2020 Apr 3.

Authors

Guodong Shen¹, Qian Gao², Fenfen Liu³, Yan Zhang⁴, Meng Dai³, Tingting Zhao⁵, Min Cheng³, Tingjuan Xu³, Peipei Jin⁶, Wu Yin³, Dabing Huang⁷, Haiyan Weng⁸, Wen Chen³, Huirong Ren³, Xuanxuan Mu³, Xinchun Wu³, Shilian Hu⁹

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China.
⁷ 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.
⁸ 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.
⁹ 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.

PMID: 32248976
DOI: 10.1016/j.bbrc.2020.03.154

Abstract

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.

Keywords: Epithelial ovarian cancer; HER2/neu; TCF7L2; Trastuzumab; Wnt.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Immunological / pharmacology*
Carcinoma, Ovarian Epithelial / drug therapy*
Cell Line, Tumor
Drug Resistance, Neoplasm
Female
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Lentivirus
Mice, Nude
Neoplasms, Experimental
Phosphorylation
Prognosis
RNA, Messenger / metabolism
RNA, Small Interfering / metabolism
Receptor, ErbB-2 / metabolism*
Transcription Factor 7-Like 2 Protein / genetics
Transcription Factor 7-Like 2 Protein / metabolism*
Transfection
Trastuzumab / pharmacology*
Wnt Signaling Pathway
Wnt3A Protein / metabolism*
beta Catenin / metabolism*

Substances

Antineoplastic Agents, Immunological
CTNNB1 protein, human
RNA, Messenger
RNA, Small Interfering
TCF7L2 protein, human
Transcription Factor 7-Like 2 Protein
WNT3A protein, human
Wnt3A Protein
beta Catenin
ERBB2 protein, human
Receptor, ErbB-2
Trastuzumab