Aberrantly expressed Fra-1 by IL-6/STAT3 transactivation promotes colorectal cancer aggressiveness through epithelial-mesenchymal transition.
The pro-inflammatory cytokine interleukin-6 (IL-6) in tumor microenvironment has been suggested to promote development and progression of colorectal cancer (CRC). However, the underlying molecular mechanisms remain elusive. In this study, we demonstrate that fos-related antigen-1 (Fra-1) plays a critical role in IL-6 induced CRC aggressiveness and epithelial-mesenchymal transition (EMT). In CRC cell lines, the expression of Fra-1 gene was found significantly upregulated during IL-6-driven EMT process. The Fra-1 induction occurred at transcriptional level in a manner dependent on signal transducer and activator of transcription 3 (STAT3), during which both phosphorylated and acetylated post-translational modifications were required for STAT3 activation to directly bind to the Fra-1 promoter. Importantly, RNA interference-based attenuation of either STAT3 or Fra-1 prevented IL-6-induced EMT, cell migration and invasion, whereas ectopic expression of Fra-1 markedly reversed the STAT3-knockdown effect and enhanced CRC cell aggressiveness by regulating the expression of EMT-promoting factors (ZEB1, Snail, Slug, MMP-2 and MMP-9). Furthermore, Fra-1 levels were positively correlated with the local invasion depth as well as lymph node and liver metastasis in a total of 229 CRC patients. Intense immunohistochemical staining of Fra-1 was observed at the tumor marginal area adjacent to inflammatory cells and in parallel with IL-6 secretion and STAT3 activation in CRC tissues. Together, this study proposes the existence of an aberrant IL-6/STAT3/Fra-1 signaling axis leading to CRC aggressiveness through EMT induction, which suggests novel therapeutic opportunities for the malignant disease.
Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
Hong
H
Liu
Department of Pathology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Guoping
G
Ren
Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
Tingyang
T
Wang
Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
Yuexia
Y
Chen
Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
Chaoju
C
Gong
Department of Pathology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Yanfeng
Y
Bai
Department of Pathology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Bo
B
Wang
Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
Hongyan
H
Qi
Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
Jing
J
Shen
Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
Lijun
L
Zhu
Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Cheng
C
Qian
Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
Maode
M
Lai
Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China, shaojimin@zju.edu.cn.
Jimin
J
Shao
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D004268:DNA-Binding Proteins; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D008207:Lymphatic Metastasis / Q000235:genetics; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D059016:Tumor Microenvironment; D000099169:Fos-Related Antigen 1
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D000099169:Fos-Related Antigen 1; C508600:IL6 protein, human; C494086:STAT3 protein, human