STAT1-mediated inhibition of FOXM1 enhances gemcitabine sensitivity in pancreatic cancer

被引：41

作者：

Liu, Chao ^{[1
,2
]}

Shi, Jiaqi ^{[1
,2
]}

Li, Qingwei ^{[1
,2
]}

Li, Zhiwei ^{[1
]}

Lou, Changjie ^{[1
]}

Zhao, Qi ^{[1
,2
]}

Zhu, Yuanyuan ^{[1
,2
]}

Zhan, Fei ^{[1
,2
]}

Lian, Jie ^{[1
,2
]}

Wang, Bojun ^{[1
,2
]}

Guan, Xin ^{[1
,2
]}

Fang, Lin ^{[1
]}

Li, Zengxun ^{[3
]}

Wang, Yifei ^{[3
]}

Zhou, Bodong ^{[3
]}

Yao, Yuanfei ^{[1
,2
]}

Zhang, Yanqiao ^{[1
,2
]}

机构：

[1] Harbin Med Univ Canc Hosp, Dept Gastrointestinal Med Oncol, 150 Haping Rd, Harbin 150001, Heilongjiang, Peoples R China

[2] Heilongjiang Acad Med Sci, Translat Med Res & Cooperat Ctr Northern China, 194 Xuefu Rd, Harbin 150000, Heilongjiang, Peoples R China

[3] Tianjin Med Univ Canc Inst & Hosp, Dept Pancreat Canc, Natl Clin Res Ctr Canc, Key Lab Canc Prevent & Therapy, Huan Hu Xi Rd, Tianjin 300060, Peoples R China

来源：

CLINICAL SCIENCE | 2019年 / 133卷 / 05期

基金：

中国国家自然科学基金;

关键词：

CARCINOMA PATIENTS; POOR-PROGNOSIS; IFN-ALPHA; TRANSACTIVATING ACTIVITY; SIGNALING PATHWAY; BREAST-CANCER; RESISTANCE; EXPRESSION; CELLS; ACTIVATION;

D O I：

10.1042/CS20180816

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Forkhead box protein M1 (FOXM1) was identified as an oncogenic transcription factor and master regulator of tumor progression and metastasis. FOXM1 expression often correlates with poor prognosis and chemotherapy resistance. In the present study, we investigated the association of FOXM1 expression and chemoresistance in pancreatic cancer. Elevated FOXM1 protein levels were associated with gemcitabine chemoresistance in patients with pancreatic cancer. In gemcitabine resistance cell line models of pancreatic cancer, FOXM1 expression increased, which induced gemcitabine chemoresistance in vitro. In pancreatic cancer cells treated with gemcitabine, FOXM1 affected nuclear factor kappa B (NF-kappa B) signaling activity. Immunohistochemical analysis demonstrated a negative association of FOXM1 expression and the level of phosphorylated signal transducer and activator of transcription 1 (pSTAT1) in human pancreatic cancer tissues. Dual-luciferase reporter assays and chromatin-immunoprecipitation assays demonstrated that pSTAT1 directly binds to the FOXM1 promoter to down-regulate its transcription. Interferon gamma (IFN gamma) promoted gemcitabine-induced cell apoptosis and inhibited cell proliferation in vitro and in vivo by FOXM1 inhibition. These data suggested that FOXM1 enhances chemoresistance to gemcitabine in pancreatic cancer. IFN gamma could be used to down-regulate the expression of FOXM1 through STAT1 phosphorylation, thereby increasing the sensitivity of pancreatic cancer cells to gemcitabine. These studies suggested the sensitization by IFN gamma in pancreatic ductal adenocarcinoma (PDAC) chemotherapy, which requires further clinical studies.

引用

页码：645 / 663

页数：19

共 56 条

[1]

Arlt A, 2002, INT J CLIN PHARM TH, V40, P336

[2] Tight correlation between expression of the Forkhead transcription factor FOXM1 and HER2 in human breast cancer [J].