Oncotarget

Research Papers:

IL-13/STAT6 signaling plays a critical role in the epithelial-mesenchymal transition of colorectal cancer cells

Hui Cao, Jing Zhang, Hong Liu, Ledong Wan, Honghe Zhang, Qiong Huang, Enping Xu and Maode Lai _

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Oncotarget. 2016; 7:61183-61198. https://doi.org/10.18632/oncotarget.11282

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Abstract

Hui Cao1,2,3,*, Jing Zhang1,2,*, Hong Liu1,4, Ledong Wan1,2, Honghe Zhang1,2, Qiong Huang1,2, Enping Xu1,2, Maode Lai1,2

1Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310058, China

2Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou 310058, China

3Department of Pathology and Pathophysiology, Cheng Du Medical College, Chengdu 610500, China

4Jinhua People’s Hospital, Jinhua Polytechnic College, Jinhua 321000, China

*These authors have contributed equally to this work

Correspondence to:

Maode Lai, email: [email protected]

Enping Xu, email: [email protected]

Keywords: colorectal cancer, interleukin-13, STAT6, ZEB1, EMT

Received: December 13, 2015     Accepted: August 08, 2016     Published: August 13, 2016

ABSTRACT

Colorectal cancer (CRC) is one of the most common causes of cancer-related death worldwide due to the distant metastases. Compelling evidence has reported that epithelial-mesenchymal transition (EMT) is involved in promoting cancer invasion and metastasis. However, the precise molecular events that initiate this complex EMT process remain poorly understood. Here, we showed that the pleiotropic cytokine interleukin-13 (IL-13) could induce an aggressive phenotype displaying EMT by enhancing the expression of EMT-promoting factor ZEB1. Importantly, STAT6 signaling inhibitor and STAT6 knockdown significantly reversed IL-13-induced EMT and ZEB1 induction in CRC cells, whereas ectopic STAT6 expression in STAT6null CRC cell line markedly promoted EMT in the present of IL-13. ChIP-PCR and Luciferase assays revealed that activated STAT6 directly bound to the promoter of ZEB1. Otherwise, we found IL-13 also up-regulated the stem cell markers (nanog, CD44, CD133 and CD166) and promoted cell migration and invasion through STAT6 pathway. We also found that siRNA-mediated knockdown of IL-13Rα1 could reverse IL-13-induced ZEB1 and EMT changes by preventing STAT6 signaling. Finally, we demonstrated positive correlation between IL-13Rα1 and ZEB1 at mRNA levels in human CRC samples. Taken together, our findings first demonstrated that IL-13/IL-13Rα1/STAT6/ZEB1 pathway plays a critical role in promoting EMT and aggressiveness of CRC.


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