Integrin α9 depletion promotes β-catenin degradation to suppress triple-negative breast cancer tumor growth and metastasis

Zhishan Wang, Yunfei Li, Yajuan Xiao, Hsuan Pei Lin, Ping Yang, Brock Humphries, Tianyan Gao, Chengfeng Yang

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Although integrin α9 (ITGA9) is known to be involved in cell adhesion and motility, its expression in cancer and its role in tumor growth and metastasis remain largely unknown. Our study was designed to investigate the role of ITGA9 in triple-negative breast cancer (TNBC). ITGA9 expression in TNBC cells was knocked out (KO) using CRISPR/Cas9 technology. Four orthotopic mouse mammary xenograft tumor models coupled with cell culture studies were performed to determine the effect of ITGA9 depletion on TNBC tumor growth and metastasis and the underlying mechanism. Bioinformatics analysis showed that ITGA9 level is significantly higher in TNBC than other breast cancer subtypes, and higher ITGA9 level is associated with significantly worse distant metastasis-free survival and recurrence-free survival in TNBC patients. Experimentally, ITGA9 KO significantly reduced TNBC cell cancer stem cell (CSC)-like property, tumor angiogenesis, tumor growth and metastasis by promoting β-catenin degradation. Further mechanistic studies revealed that ITGA9 KO causes integrin-linked kinase (ILK) relocation from the membrane region to the cytoplasm, where it interacts with protein kinase A (PKA) and inhibits PKA activity leading to increased activity of glycogen synthase kinase 3 (GSK3) and subsequent β-catenin degradation. Overexpressing β-catenin in ITGA9 KO cells reversed the inhibitory effect of ITGA9 KO on tumor growth and metastasis. Furthermore, ITGA9 downregulation in TNBC tumors by nanoparticle-mediated delivery of ITGA9 siRNA drastically decreased tumor angiogenesis, tumor growth and metastasis. These findings indicate that ITGA9 depletion suppresses TNBC tumor growth and metastasis by promoting β-catenin degradation through the ILK/PKA/GSK3 pathway.

Original languageEnglish
Pages (from-to)2767-2780
Number of pages14
JournalInternational Journal of Cancer
Volume145
Issue number10
DOIs
StatePublished - Nov 15 2019

Bibliographical note

Funding Information:
Our study was supported in part by a Research Scholar Grant (RGS-15-026-01-CSM) from the American Cancer Society to C.Y., a research grant from Elsa U. Pardee Foundation to Z.W., and a NIH grant (R01CA133429) to G.T. This research was also supported by the Shared Animal Imaging and Histology Resources of the University of Kentucky Markey Cancer Center (P30CA177558) and The University of Kentucky Center for Appalachian Research in Environmental Sciences Center grant (1P30ES026529-01A1).

Publisher Copyright:
© 2019 UICC

Keywords

  • integrin α9
  • integrin-linked kinase
  • metastasis
  • protein kinase A
  • triple-negative breast cancer
  • β-catenin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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