Cancer-associated fibroblasts promote progression and gemcitabine resistance via the SDF-1/SATB-1 pathway in pancreatic cancer

被引：141

作者：

Wei, Lusheng ^{[1
,2
]}

Ye, Huilin ^{[1
,2
]}

Li, Guolin ^{[1
,2
]}

Lu, Yuanting ^{[3
]}

Zhou, Quanbo ^{[1
,2
]}

Zheng, Shangyou ^{[1
,2
]}

Lin, Qing ^{[1
,2
]}

Liu, Yimin ^{[1
,4
]}

Li, Zhihua ^{[1
,5
]}

Chen, Rufu ^{[1
,2
]}

机构：

[1] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Guangdong Prov Key Lab Malignant Tumor Epigenet &, Guangzhou, Guangdong, Peoples R China

[2] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Pancreatobiliary Surg, Guangzhou, Guangdong, Peoples R China

[3] Guangzhou Med Univ, Guangzhou Women & Childrens Med Ctr, Dept Radiol, Guangzhou, Guangdong, Peoples R China

[4] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Radiotherapy, Guangzhou, Guangdong, Peoples R China

[5] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Med Oncol, Guangzhou, Guangdong, Peoples R China

来源：

CELL DEATH & DISEASE | 2018年 / 9卷

基金：

中国国家自然科学基金;

关键词：

CHROMATIN ORGANIZER SATB1; CXCL12/CXCR4; AXIS; BINDING-PROTEIN; POOR SURVIVAL; UP-REGULATION; TUMOR-GROWTH; EXPRESSION; METASTASIS; INVASION; MARKER;

D O I：

10.1038/s41419-018-1104-x

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Cancer-associated fibroblasts (CAFs), a dominant component of the pancreatic tumor microenvironment, are mainly considered as promotors of malignant progression, but the underlying molecular mechanism remains unclear. Here, we show that SDF-1 secreted by CAFs stimulates malignant progression and gemcitabine resistance in pancreatic cancer, partially owing to paracrine induction of SATB-1 in pancreatic cancer cells. CAF-secreted SDF-1 upregulated the expression of SATB-1 in pancreatic cancer cells, which contributed to the maintenance of CAF properties, forming a reciprocal feedback loop. SATB-1 was verified to be overexpressed in human pancreatic cancer tissues and cell lines by quantitative real-time PCR, western blot, and immunohistochemical staining, which correlated with tumor progression and clinical prognosis in pancreatic cancer patients. We found that SATB-1 knockdown inhibited proliferation, migration, and invasion in SW1990 and PANC-1 cells in vitro, whereas overexpression of SATB-1 in Capan-2 and BxPC-3 cells had the opposite effect. Immunofluorescence staining showed that conditioned medium from SW1990 cells expressing SATB-1 maintained the local supportive function of CAFs. Furthermore, downregulation of SATB-1 inhibited tumor growth in mouse xenograft models. In addition, we found that overexpression of SATB-1 in pancreatic cancer cells participated in the process of gemcitabine resistance. Finally, we investigated the clinical correlations between SDF-1 and SATB-1 in human pancreatic cancer specimens. In summary, these findings demonstrated that the SDF-1/CXCR4/SATB-1 axis may be a potential new target of clinical interventions for pancreatic cancer patients.

引用

页数：17