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Int J Biochem Cell Biol. 2019 Mar;108:84-91. doi: 10.1016/j.biocel.2019.01.011. Epub 2019 Jan 18.

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

Author information

1
Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
2
Department of Hepatobiliary pancreatic surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
3
Organ Transplantation Center, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China.
4
Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: jinxinunion@hust.edu.cn.
5
Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: heshuiwu@hust.edu.cn.

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.

KEYWORDS:

B7-H3; BET inhibitors; BRD4; Pancreatic ductal adenocarcinoma (PDAC); TLR4

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