A comprehensive analysis of different types of databases reveals that CDH1 mRNA and E-cadherin protein are not downregulated in most carcinoma tissues and carcinoma cell lines.

BACKGROUND: The CDH1 gene codes for the epithelial-cadherin (E-cad) protein, which is embedded in the plasma membrane of epithelial cells to form adherens junctions. E-cad is known to be essential for maintaining the integrity of epithelial tissues, and the loss of E-cad has been widely considered a hallmark of metastatic cancers enabling carcinoma cells to acquire the ability to migrate and invade nearby tissues. However, this conclusion has come under scrutiny. METHODS: To assess how CDH1 and E-cad expression changes during cancer progression, we analyzed multiple large transcriptomics, proteomics, and immunohistochemistry datasets on clinical cancer samples and cancer cell lines to determine the CDH1 mRNA and E-cad protein expression profiles in tumor and normal cells. RESULTS: In contrast to the textbook knowledge of the loss of E-cad during tumor progression and metastasis, the levels of CDH1 mRNA and E-cad protein are either upregulated or remain unchanged in most carcinoma cells compared to normal cells. In addition, the CDH1 mRNA upregulation occurs in the early stages of tumor development and the levels remain elevated as tumors progress to later stages across most carcinoma types. Furthermore, E-cad protein levels are not downregulated in most metastatic tumor cells compared to primary tumor cells. The CDH1 mRNA and E-cad protein levels are positively correlated, and the CDH1 mRNA levels are positively correlated to cancer patient's survival. We have discussed potential mechanisms underlying the observed expression changes in CDH1 and E-cad during tumor progression. CONCLUSIONS: CDH1 mRNA and E-cadherin protein are not downregulated in most tumor tissues and cell lines derived from commonly occurring carcinomas. The role of E-cad in tumor progression and metastasis may have previously been oversimplified. CDH1 mRNA levels may serve as a reliable biomarker for the diagnosis of some tumors (such as colon and endometrial carcinomas) due to the marked upregulation of CDH1 mRNA in the early stages of tumor development of these carcinomas.

Upregulation of CD73 Confers Acquired Radioresistance and is Required for Maintaining Irradiation-selected Pancreatic Cancer Cells in a Mesenchymal State.

The molecular mechanisms underlying exceptional radioresistance in pancreatic cancer remain elusive. In the present study, we established a stable radioresistant pancreatic cancer cell line MIA PaCa-2-R by exposing the parental MIA PaCa-2 cells to fractionated ionizing radiation (IR). Systematic proteomics and bioinformatics analysis of protein expression in MIA PaCa-2 and MIA PaCa-2-R cells revealed that several growth factor-/cytokine-mediated pathways, including the OSM/STAT3, PI3K/AKT, and MAPK/ERK pathways, were activated in the radioresistant cells, leading to inhibition of apoptosis and increased epithelial-mesenchymal plasticity. In addition, the radioresistant cells exhibited enhanced capabilities of DNA repair and antioxidant defense compared with the parental cells. We focused functional analysis on one of the most up-regulated proteins in the radioresistant cells, ecto-5'-nucleotidase (CD73), which is a cell surface protein that is overexpressed in different types of cancer. Ectopic overexpression of CD73 in the parental cells resulted in radioresistance and conferred resistance to IR-induced apoptosis. Knockdown of CD73 re-sensitized the radioresistant cells to IR and IR-induced apoptosis. The effect of CD73 on radioresistance and apoptosis is independent of the enzymatic activity of CD73. Further studies demonstrate that CD73 up-regulation promotes Ser-136 phosphorylation of the proapoptotic protein BAD and is required for maintaining the radioresistant cells in a mesenchymal state. Our findings suggest that expression alterations in the IR-selected pancreatic cancer cells result in hyperactivation of the growth factor/cytokine signaling that promotes epithelial-mesenchymal plasticity and enhancement of DNA repair. Our results also suggest that CD73, potentially a novel downstream factor of the enhanced growth factor/cytokine signaling, confers acquired radioresistance by inactivating proapoptotic protein BAD via phosphorylation of BAD at Ser-136 and by maintaining the radioresistant pancreatic cancer cells in a mesenchymal state.