The Wnt3a/β-catenin/TCF7L2 signaling axis reduces the sensitivity of HER2-positive epithelial ovarian cancer to trastuzumab.
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
Transfection
Trastuzumab
/ pharmacology
Wnt Signaling Pathway
Wnt3A Protein
/ metabolism
beta Catenin
/ metabolism
Epithelial ovarian cancer
HER2/neu
TCF7L2
Trastuzumab
Wnt
Journal
Biochemical and biophysical research communications
ISSN: 1090-2104
Titre abrégé: Biochem Biophys Res Commun
Pays: United States
ID NLM: 0372516
Informations de publication
Date de publication:
04 06 2020
04 06 2020
Historique:
received:
23
03
2020
accepted:
26
03
2020
pubmed:
7
4
2020
medline:
18
12
2020
entrez:
7
4
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32248976
pii: S0006-291X(20)30651-3
doi: 10.1016/j.bbrc.2020.03.154
pii:
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
CTNNB1 protein, human
0
RNA, Messenger
0
RNA, Small Interfering
0
TCF7L2 protein, human
0
Transcription Factor 7-Like 2 Protein
0
WNT3A protein, human
0
Wnt3A Protein
0
beta Catenin
0
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Trastuzumab
P188ANX8CK
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
685-691Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.