The endoplasmic reticulum stress marker CHOP predicts survival in malignant mesothelioma

Abstract

Background:Mesothelioma is an incurable cancer originating from the mesothelial cells that line the pleural, peritoneal and pericardial cavities. These cells synthesise large quantities of surface glycoproteins, rendering them dependent upon efficient endoplasmic reticulum (ER) function. When faced with elevated levels of secretory protein load, cells are said to experience ER stress, which has been implicated in the pathogenesis of many human diseases including cancer.Method:We set out to measure markers of ER stress in malignant mesothelioma and to determine whether ER stress signalling correlates with clinical parameters.Results:We observed that expression of the ER stress-responsive transcription factor C/EBP homologous protein (CHOP) correlated with patient survival and remained an independent prognostic variable in pairwise comparisons with all clinical variables tested. The most parsimonious multivariate model in our study comprised only performance status and CHOP staining. In contrast, expression of the ER stress-responsive phosphatase growth arrest and DNA damage 34 (GADD34) correlated with the degree of mesothelial differentiation, being lost progressively in biphasic and sarcomatoid mesotheliomas.Conclusion:Our findings suggest that staining for CHOP provides prognostic information that may be useful in the stratification of patients with mesothelioma. Staining for GADD34 may prove useful in classification of mesothelioma histopathology.

Endoplasmic reticulum stress in lung disease

“…Accordingly, in murine medulloblastoma, loss of GADD34 enhances eIF2α phosphorylation, thus promoting tumour growth, invasiveness and angiogenesis [50]. We showed in malignant mesothelioma that low expression of GADD34 correlates with increased tumour aggression [9]. It is therefore possible that agents that inhibit PERK or restore GADD34 function might prove beneficial in treating thoracic malignancy.…”

Knockdown of S100P by lentiviral-mediated RNAi promotes apoptosis and suppresses the colony-formation ability of gastric cancer cells

“…DDIT3 (also known as CHOP, GADD153), upregulated in the S100P-knockdown cells, is considered a key event in endoplasmic reticulum stress-mediated apoptosis (25). Expression of the ER stress-responsive transcription factor CHOP was found to be correlated with patient survival and remained an independent prognostic variable in pairwise comparisons with all clinical variables tested (26). CHOP expression had no statistical difference between the mock and S100P-overexpressing cells.…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…Cancer CHOP expression in tumors correlates with stage, malignancy, and low survival in patients (Kim et al 2012;Dalton et al 2013). The incidence of K-ras (G12V)-induced lung cancer is markedly enhanced in the absence of CHOP (Huber et al 2013), suggesting an anticancer activity of CHOP.…”