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

Jingyuan Zhao; Zibo Meng; Chao Xie; Chong Yang; Zhiqiang Liu; Shihong Wu; Bo Wang; Ping Fan; Xin Jin; Heshui Wu

doi:10.1016/j.biocel.2019.01.011

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

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

Authors

Jingyuan Zhao¹, Zibo Meng¹, Chao Xie², Chong Yang³, Zhiqiang Liu¹, Shihong Wu¹, Bo Wang¹, Ping Fan¹, Xin Jin⁴, Heshui Wu⁵

Affiliations

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.

PMID: 30664982
DOI: 10.1016/j.biocel.2019.01.011

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
B7 Antigens / metabolism*
Carcinoma, Pancreatic Ductal / pathology*
Cell Cycle Proteins
Cell Line, Tumor
Cell Proliferation
Gene Expression Regulation, Neoplastic*
Humans
Nuclear Proteins / metabolism*
Signal Transduction
Toll-Like Receptor 4 / genetics*
Transcription Factors / metabolism*

Substances

B7 Antigens
BRD4 protein, human
CD276 protein, human
Cell Cycle Proteins
Nuclear Proteins
Toll-Like Receptor 4
Transcription Factors