CCN1 induces a reversible epithelial–mesenchymal transition in gastric epithelial cells

Abstract

CCN1 is a matricellular protein that activates many genes related to wound healing and tissue remodeling in fibroblasts, but its effect on epithelial cells remains unclear. This study examined the role of CCN1 in epithelial wound healing using rat gastric epithelial cells and rat stomach ulcer as in vitro and in vivo models, respectively. We found that CCN1 expression is highly upregulated in the epithelial cells adjacent to a wound and remains high until the wound is healed. Upregulation of CCN1 activates a transient epithelial-mesenchymal transition in the epithelial cells at the migrating front and drives wound closure. Once the wound is healed, these epithelial cells and their progeny can resume their original epithelial phenotype. We also found that CCN1-induced E-cadherin loss is not due to transcriptional regulation but rather protein degradation due to the collapse of adherens junctions, which is contributed by b-catenin translocation. CCN1-activated integrin-linked kinase mediates this process. Finally, our in vivo study showed that locally neutralizing CCN1 drastically impairs wound closure, whereas local injection of recombinant CCN1 protein induces expression of vimentin and smooth muscle a-actin in normal gastric mucosal epithelial cells and accelerates re-epithelialization during ulcer healing. In conclusion, our study indicates that CCN1 can induce reversible epithelial-mesenchymal transition, and this feature may have great value for clinical wound healing.

IGF-1 Regulates Cyr61 Induced Breast Cancer Cell Proliferation and Invasion

“…E-cadherin is a well-established “gate-keeper” for cell-adhesion and loss has been associated with epithelial mesenchymal transition and increased invasiveness [30]–[32]. Loss of E-cadherin in response to Cyr61 has been shown in Cyr61 induction studies in gastric cancer [33], however, we are among the first to report these findings in breast cancer.…”

“…Cyr61 has been shown to bind with integrins such as αvβ5 and α3β5, in the extracellular matrix space [37]. Integrin binding has been shown to induce actin filament rearrangement which can contribute to morphological changes- such as epithelial-mesenchymal transition [33]. Menendez and colleagues have demonstrated in several studies that targeting the αβ integrins in Cyr61 overexpressing breast cells successfully restores drug-response [26], [38].…”

Androgen Glucuronidation: An Unexpected Target for Androgen Deprivation Therapy, with Prognosis and Diagnostic Implications

“…Microarrays and immunohistochemical (IHC) stains were obtained as previously described (24,25), with formalin-fixed and paraffin-embedded 4-mm sections of the microarray, using the previously described (22,23,26) polyclonal anti-vimentin (positive control; 1:100 dilution), anti-UGT2B15 (1:300 dilution), and anti-UGT2B17 (1:150 dilution) antibodies (Supplementary SM2-8). The IHC staining (Supplementary SM2-8) was scored by a pathologist (L. Fazli) for the level of immunoexpression on a scale from 0 to 3, wherein 0 was undetectable, 1 represented a faint or focal questionably present stain, 2 represented a stain of convincing intensity in a minority of cells, and 3 represented a stain of convincing intensity in a majority of cells.…”

Gastric Ulcer Healing – Role of Serum Response Factor

“…In addition to being an angiogenic factor, CCN1 also supports cell adhesion, migration, proliferation, differentiation and survival. Recently, we have found that CCN1 is highly up-regulated in the gastric epithelial cells adjacent to the ulcer and remains high until the wound is healed (Figure 7; Chai et al, 2010b). This was demonstrated by epithelial injury both in vivo (gastric ulcer margin) and in vitro (gastric epithelial cell culture).…”