PO-301 Protein disulfide isomerase A4 regulates cancer development via cancer stromal cells

Abstract

IntroductionProtein disulfide isomerases represent a family of multifunctional enzymes. One of their roles is implicated in the growth and death of tumour cells. Our publication showed that protein disulfide isomerase a4 (PDIA4) negatively regulated tumour cell apoptosis by inhibiting degradation and activation of procaspases 3 and 7. However, its impact in cancer development is not clear. This study aims to characterise the pro-cancer action and mechanism of PDIA4 in tumour microenvironment.Material and methodsPDIA4 knockout and wild-type control mice were generated to identify the action and mechanism of host PDIA4 in tumor-bearing mice. GFP-expressing Lewis lung carcinoma cells were subcutaneously injected into B6 mice as a mouse model of lung cancer. Function of cancer stromal cells such as angiogenesis and immune tolerance were evaluated by immunohistochemistry, flow cytometry, and Western blotting. Dual luciferase reporter assay were used to further confirm the molecular target of PDIA4 in cancer stromal cells.Results and discussionsWe found that PDIA4 is up-regulated in cancer stromal cells as well as tumour cells, as shown by Real-time PCR and immunoblot. Consistently, oncomine database showed that PDIA4 expression level is positively correlated to the prognosis and metastasis in patients with different types of cancer. Knockout of host PDIA4 in tumor-bearing mice reduced tumour development, metastasis and angiogenesis. This reduction was relevant to the composition and function of cancer stromal populations. We are on the process of identify the cellular and molecular mechanism of PDIA4 in tumour microenvironment.ConclusionThis study demonstrates that PDIA4 can not only work on tumour cells but also regulate tumour microenvironment. The data suggest that PDIA4 is a potential therapeutic target for cancer.