B7-H3 is regulated by BRD4 and promotes TLR4 expression in pancreatic ductal adenocarcinoma.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide. PDAC is resistant to chemotherapy and radiotherapy which leads to the poor prognosis of PDAC patients and a 5-year survival rate of less than 5%. Exploring the mechanism of the pancreatic cancer tumorigenesis is the key to finding a novel therapeutic strategy for cancer treatment. B7-H3 belongs to the B7 family of immunoregulatory proteins, and the overexpression of B7-H3 is found in various types of cancer. The regulation of B7-H3 expression in pancreatic cancer is still unclear. Here, we showed that B7-H3 acted as a negative prognostic biomarker in PDAC and promoted cell proliferation, invasion and metastasis in pancreatic cancer. Next, we applied the drug screening method to identify bromodomain and extra-terminal motif (BET) inhibitors that decreased the protein and mRNA levels of B7-H3 in pancreatic cancer cells. Moreover, we verified that BRD4 was responsible for regulating the expression of B7-H3 at the transcriptional level. Finally, our data indicated that the BRD4/B7-H3 axis modulated the expression of TLR4 in pancreatic cancer cells. Taken together, our results elucidated the regulation of B7-H3 expression in pancreatic cancer and uncovered the importance of BRD4/B7-H3/TLR4 pathway. The targeting of B7-H3 by the BET inhibitors may be a novel therapeutic strategy to overcome the immunotherapy and chemotherapy resistance in pancreatic cancer.