B7-H3 is regulated by BRD4 and promotes TLR4 expression in pancreatic ductal adenocarcinoma. (March 2019)

• Record Type: Journal Article
• Authors: Zhao, Jingyuan; Meng, Zibo; Xie, Chao; Yang, Chong; Liu, Zhiqiang; Wu, Shihong; Wang, Bo; Fan, Ping; Jin, Xin; Wu, Heshui
• Is Part Of: International journal of biochemistry & cell biology. Volume 108(2019)
• Page Start: 84
• Page End: 91
• Publication Date: 2019-03
• Subjects: Pancreatic ductal adenocarcinoma (PDAC) -- BET inhibitors -- B7-H3 -- BRD4 -- TLR4; Biochemistry -- Periodicals; Cytology -- Periodicals; Biochemistry -- Periodicals; Cell Biology -- Periodicals; Biochimie -- Périodiques; Cytologie -- Périodiques; Biochimie; Cytologie; Biochemistry; Cytology; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); Periodicals; 572.05
• DOI: 10.1016/j.biocel.2019.01.011
• Languages: English
• ISSNs: 1357-2725

Abstract

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.