Protein Disulfide Isomerase A4 Promotes Lung Cancer Development Via the Stat3 Pathway in Stromal Cells

AbstractBackgroundProtein disulfide isomerases a4 (Pdia4) is known to be involved in cancer development. Our previous publication showed that Pdia4 positively promotes cancer development via its inhibition of procaspase‐dependent apoptosis in cancer cells. However, nothing is known about its role in the cancer microenvironment.ResultsHere, we first found that Pdia4 expression in lung cancer was negatively correlated with patient survival. Next, we investigated the impact of host Pdia4 in stromal cells during cancer development. We showed that Pdia4 was expressed at a low level in stromal cells, and this expression was up‐regulated akin to its expression in cancer cells. This up‐regulation was stimulated by tumour cell‐derived stimuli. Genetics studies in tumour‐bearing wild‐type and Pdia4–/– mice showed that host Pdia4 promoted lung cancer development in the mice via cancer stroma. This promotion was abolished in Rag1–/– mice which lacked T and B cells. This promotion could be restored once T and B cells were added back to Rag1–/– mice. In addition, host Pdia4 positively regulated the number and immunosuppressive function of stromal cells. Mechanistic studies showed that host Pdia4 positively controlled the Stat3/Vegf pathway in T and B lymphocytes via its stabilization of activated Stat3 in a Thioredoxin‐like domain (CGHC)‐dependent manner.ConclusionsThese findings identify Pdia4 as a possible target for intervention in cancer stroma, suggesting that targeting Pdia4 in cancer stroma is a promising anti‐cancer approach.