Cristina Modak

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

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 β-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 α-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.

Casein Kinase I epsilon positively regulates the Akt pathway in breast cancer cell lines.

The Akt pathway is very important in both development and cancer. Here we show that, expression of Casein Kinase I epsilon (CKIepsilon) causes up-regulation of the Akt pathway despite normal protein expression of the pathway inhibitor phosphate and tensin homologue deleted on chromosome ten (PTEN). Conversely, we show that a CKIepsilon/delta-specific inhibitor can inhibit Akt phosphorylation at both Thr308 and Ser473 and drastically reduce phosphorylation of the Akt target Glycogen Synthase Kinase 3beta (GSK3beta). These conclusions were confirmed between MCF7 cells transiently transfected with CKIepsilon and Hs578T cells which already express endogenous CKIepsilon. The results suggest that CKIepsilon is a new positive regulator of the Akt pathway. Here we propose that, rather than inhibiting PTEN function, CKIepsilon positively regulates Akt possibly by inhibiting Protein Phosphatase 2A (PP2A).

Potential of casein kinase I in digestive cancer screening

Casein kinase I is a group of ubiquitous Serine/Threonine kinases that have been implicated in both normal cellular functions and several pathological conditions including Alzheimers disease and cancer. Recent findings in colon and pancreatic cancer have brought tremendous attention to these molecules as potential therapeutic targets in treatment of digestive cancers. In this review, we summarize up to date what is known about this family of kinases and their involvement in carcinogenesis and other pathological conditions. Our emphasis is on their implications in digestive cancers and their potential for cancer screening and therapy.

CCN1 is critical for acid-induced esophageal epithelial cell transformation

CCN1 is a matricellular protein involved in both wound healing and cancer cell invasion. Increased CCN1 expression has been associated with the development of Barretts esophagus and the increased risk of progression to esophageal adenocarcinoma. In both cases, acid reflux is a major contributor. Low pH has been shown to induce CCN1 gene expression in esophageal epithelial cells. Here we demonstrated that both CCN1 and low pH could cause esophageal epithelial cell transformation, including loss of E-cadherin, disruption of cell-cell junctions, and expression of mesenchymal markers. Furthermore, knockdown of CCN1 through RNA interference sufficiently attenuated acid-driven cell phenotypic changes, while over-expression of CCN1 exacerbated these effects, indicating a critical role of CCN1 in acid-induced esophageal epithelial cell transformation. Given the pivotal role of low pH in gastro-esophageal reflux disease and its progression towards esophageal adenocarcinoma, our study identified CCN1 as a key molecule mediating this process.

CCN1 sensitizes esophageal cancer cells to TRAIL-mediated apoptosis

Abstract TRAIL is one of the best anti‐cancer molecules in our body. It kills a variety of cancer cells that are resistant to conventional chemotherapy, without causing much negative impact on normal cells, because its death receptors are almost exclusively found on cancer cells. However, some cancer cells are not sensitive to TRAIL treatment, even though they express its death receptors. A second molecule is needed to help TRAIL to complete its mission. Finding such molecules now becomes a top priority in cancer research. Our study shows that CCN1 is such a molecule. CCN1 was highly expressed in the esophageal epithelium of the patients suffering from gastroesophageal reflux disease, but faded away as the situation worsened towards adenocarcinoma. Treating the tumor cells with CCN1 resulted in apoptosis, while the same treatment to the normal cells only nourished cell growth. It was TRAIL that mediated this process. Apparently, CCN1 altered the expression profile of TRAIL and its receptors in tumor cells, namely, activating TRAIL and its death receptors and shutting down its decoy receptors. CCN1 and TRAIL worked as a team to put the cancer cells to death, as elimination of either one failed apoptosis. Graphical abstract Figure. No Caption available. HighlightsEAC cells express all three decoy receptors of TRAIL.CCN1 is barely detectable in EAC cells.CCN1 inhibits expression of TRAIL decoy receptors in EAC cells.CCN1 induces apoptosis in EAC cells.TRAIL mediates CCN1‐induced EAC cell apoptosis.

CCN1 induces apoptosis in esophageal adenocarcinoma through p53-dependent downregulation of survivin: DANG et al.

Many cancer drugs have been developed to control tumor growth by inducing cancer cell apoptosis. However, several intracellular barriers could fail this attempt. One of these barrier is high expression of survivin. Survivin can interfere caspase activation and thereby abort apoptosis. In this study, we found that CCN1 suppressed the survivin expression in tumor cells of esophageal adenocarcinoma (EAC) and thus allowed apoptosis to finish. Furthermore, we demonstrated that this downregulation was dependent on p53 phosphorylation at Ser20, and CCN1 induced EAC cell apoptosis through the activation of p53.