Integrin α7 Binds Tissue Inhibitor of Metalloproteinase 3 to Suppress Growth of Prostate Cancer Cells

Abstract

Integrin α7 (ITGA7) is a tumor-suppressor gene that is critical for suppressing the growth of malignant tumors; however, the mechanisms allowing ITGA7 to suppress the growth of cancer cells remain unclear. Herein, we show that ITGA7 binds to tissue inhibitor of metalloproteinase 3 (TIMP3) in prostate cancer cells. The ITGA7-TIMP3 binding led to a decreased protein level of tumor necrosis factor α, cytoplasmic translocation of NF-κB, and down-regulation of cyclin D1. These changes led to an accumulation of cells in G0/G1 and a dramatic suppression of cell growth. Knocking down TIMP3 or ITGA7/TIMP3 binding interference largely abrogated the signaling changes induced by ITGA7, whereas a mutant ITGA7 lacking TIMP3 binding activity had no tumor-suppressor activity. Interestingly, knocking down ITGA7 ligand laminin β1 enhanced ITGA7-TIMP3 signaling and the downstream tumor-suppressor activity, suggesting the existence of a counterbalancing role between extracellular matrix and integrin signaling. As a result, this report demonstrates a novel and critical signaling mechanism of ITGA7, through the TIMP3/NF-κB/cyclin D1 pathway.

Epigenetic down‐regulation of integrin α7 increases migratory potential and confers poor prognosis in malignant pleural mesothelioma

“…In addition to its role in the regulation of cell adhesion to the basement membrane and thus decreasing cell migration in tumour cells, ITGA7 activation also increases the level of proteins that inhibit cell cycle progression (eg CDKN3 and RACGAP1) . In prostate cancer cells, ITGA7 inhibited proliferation by down‐regulating cyclin D1 and promoted cell death via the serine protease high temperature requirement A2 (HtrA2), providing further evidence for its tumour suppressor function . Although we could not detect a correlation between proliferation and ITGA7 expression level in vitro (data not shown), the inverse correlation between ITGA7 and Ki‐67 staining was statistically significant in the patient samples.…”

Predictive value of integrin α7 for acute myeloid leukemia risk and its correlation with prognosis in acute myeloid leukemia patients

“…Integrin, large and complex transmembrane glycoproteins belonging to adhesion receptors, modulates various cell functions upon ligand binding, which serve as mechanosensors and mechanotransducers of the extracellular environment . As one of common members of the integrin family, ITGA7 is a kind of primary extracellular matrix receptor and could use its β1 chain to form heterodimers, subsequently transducing signals from the matrix to cells, which has been discovered to promote tumor progression of different carcinomas via multiple pathways . For instance, an appealing study shows that ITGA7 binds with S100P to activate focal adhesion kinase (FAK)/serine protein kinase (AKT)‐ zinc finger E‐box Binding Homeobox 1 (ZEB1) signaling way, which thereby promotes cell migration and cell invasion in lung cancer .…”

Integrin α7 knockdown suppresses cell proliferation, migration, invasion and endothelium-mesenchymal transformation in hepatocellular carcinoma

“…Integrin family is one of transmembrane protein receptors attaching cells to the extracellular matrix and binding ligands secreted by other cells [7,8]. Serving as one of family members of integrins, ITGA7 have been determined as a vital role in tumor propagation and CSCs properties regulation [5,9].…”