Overexpression of molecule GRP94 favors tumor progression in lung adenocarcinoma by interaction with regulatory T cells

摘要

BACKGROUND:Endoplasmic reticulum stress exists within a tumor. Glucose-regulated protein 94 (GRP94) is a stress-induced chaperone protein involved in tumor development and progression. Its role in myeloma, colon cancer, and other tumors has been confirmed, but its role in lung cancer is unclear. This study aimed to determine the role of GRP94 in lung cancer progression and prognostic prediction.METHODS:Immunohistochemical staining of GRP94 in human lung adenocarcinoma (AD) and corresponding normal tissue was performed, and its relationship with FOXP3sup+/sup regulatory T-cell (Treg) infiltration analyzed. We investigated the role of GRP94 in the behavior of lung AD cells by inhibiting GRP94 expression in A549 cells. Western blotting was used to detect the TGF-β/SMAD2 signaling molecules and explore the possible molecular mechanism of GRP94.RESULTS:GRP94 mRNA (encoded by HSP90B1) and protein levels were upregulated and elevated, respectively, in lung AD compared to normal lung tissues. High GRP94 expression was associated with an advanced disease stage and poor survival. There was a positive correlation between GRP94 expression and FOXP3sup+/sup Treg infiltration into lung AD tissues. Our results confirm that GRP94 knockdown inhibits cell proliferation and promotes cell apoptosis by increasing caspase-7 and CHOP levels in lung AD cells. TGF-β and SMAD2 protein levels were decreased after GRP94 depletion.CONCLUSIONS:Our study revealed that that GRP94 expression in lung AD favors tumor progression and predicts poor prognosis. The oncogenic role of GRP94 may involve inducing Treg infiltration by promoting the TGF-β signaling pathway.KEY POINTS:GRP94 protein levels were elevated in lung AD tissues compared to normal lung tissues. The high expression of GRP94 in lung AD favors tumor progression and predicts poor prognosis. The oncogenic role of the molecule GRP94 may involve the stimulation of Treg infiltration via promotion of the TGF-β signaling pathway.? 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.