Fas Signaling Promotes Gastric Cancer Metastasis through STAT3-Dependent Upregulation of Fascin

Yunshan Yang; Qiyu Zhao; Zhijian Cai; Guoping Cheng; Ming Chen; Jiaoli Wang; Haijun Zhong

doi:10.1371/journal.pone.0125132

Fas Signaling Promotes Gastric Cancer Metastasis through STAT3-Dependent Upregulation of Fascin

PLoS One. 2015 May 18;10(5):e0125132. doi: 10.1371/journal.pone.0125132. eCollection 2015.

Authors

Yunshan Yang¹, Qiyu Zhao², Zhijian Cai³, Guoping Cheng¹, Ming Chen⁴, Jiaoli Wang⁵, Haijun Zhong¹

Affiliations

¹ Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, 310022, People's Republic of China.
² Hepatobiliary & Pancreatic Intervention Center, Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, People's Republic of China.
³ Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, People's Republic of China.
⁴ Department of Otolaryngology, the Second Affiliated Hospital of School of Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, People's Republic of China.
⁵ Department of Medical Oncology, Nanjing Medical University, Affiliated Hangzhou Hospital (Hangzhou First People's Hospital), Hangzhou, 310006 People's Republic of China.

Abstract

Background: Fas signaling-activated signal transducers and activators of transcription 3 (STAT3) is required for Fascin upregulation. As an actin-bundling protein, Fascin can mediate gastric cancer (GC) cell migration.

Methods: Gastric cancer AGS cells were treated with anti-Fas (5 μg/ml) for 2 h, in order to stimulate the activation of the Fas signaling. The in vitro migration of Fas signaling-activated AGS cells was assessed using Transwell chambers. The levels of Fascin and phosphorylated STAT3 were detected by Western blotting analyses. Nude mice were injected intravenously with AGS cells treated with anti-Fas or treated with STAT3 inhibitor without anti-Fas; tumor pulmonary metastases were measured. Fascin protein expression in tumor tissues was detected by immunohistochemistry. The Fas and Fascin mRNA levels in tumor tissues from patients with GC were measured by real-time PCR and their correlation was analyzed.

Results: The activation of Fas signaling promoted cell migration and resulted in STAT3-dependent Fascin upregulation in AGS cells. STAT3 enhanced Fascin levels in vivo. Fascin was the mediator of Fas signaling-induced AGS cell migration in vitro and in vivo. Furthermore, there was a positive correlation between Fas and Fascin mRNA levels in tumor tissues from GC patients.

Conclusions: Fas signaling promotes GC metastasis through the STAT3/Fascin pathway, which may provide a new target for GC therapy.

Publication types

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

MeSH terms

Aged
Animals
Carrier Proteins / antagonists & inhibitors
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Cell Line, Tumor
Cell Movement
Female
Gene Knockdown Techniques
Heterografts
Humans
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / secondary*
Male
Mice
Mice, Nude
Microfilament Proteins / antagonists & inhibitors
Microfilament Proteins / genetics
Microfilament Proteins / metabolism*
Middle Aged
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA, Neoplasm / genetics
RNA, Neoplasm / metabolism
RNA, Small Interfering / genetics
STAT3 Transcription Factor / metabolism*
Signal Transduction
Stomach Neoplasms / genetics
Stomach Neoplasms / metabolism*
Up-Regulation
fas Receptor / genetics
fas Receptor / metabolism*

Substances

Carrier Proteins
FAS protein, human
Microfilament Proteins
RNA, Messenger
RNA, Neoplasm
RNA, Small Interfering
STAT3 Transcription Factor
STAT3 protein, human
fas Receptor
fascin

Grants and funding

This work was supported by the National Natural Science Foundation of China No. 81200014 to JLW (http://www.nsfc.gov.cn/); the Natural Science Foundation of Zhejiang Province No. LY14H160011 to YSY; No. LY12C08002 to ZJC and No. LY12H13003 to MC (http://www.zjnsf.gov.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.