CD133 facilitates epithelial-mesenchymal transition through interaction with the ERK pathway in pancreatic cancer metastasis

Molecular Cancer

Research

Makoto Yoshimitsu¹  Shyuichiro Matsubara²  Yumi Miyazaki²  Qiang Ding²  Sonshin Takao²  Koichiro Tsukasa² 

[1] Department of Hematology and Immunology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, 890-8520, Kagoshima, Japan;Division of Cancer & Regenerative Medicine Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, 890-8520, Kagoshima, Japan;

关键词: Pancreatic cancer;    CD133;    Epithelial-mesenchymal transition (EMT);    ERK1/2;    N-cadherin;    Cancer metastasis;   

DOI  :  10.1186/1476-4598-13-15

 received in 2013-11-01, accepted in 2014-01-21,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundPancreatic cancer is a lethal disease due to the high incidence of metastasis at the time of detection. CD133 expression in clinical pancreatic cancer correlates with poor prognosis and metastasis. However, the molecular mechanism of CD133-regulated metastasis remains unclear. In recent years, epithelial-mesenchymal transition (EMT) has been linked to cancer invasion and metastasis. In the present study we investigated the role of CD133 in pancreatic cancer metastasis and its potential regulatory network.MethodsA highly migratory pancreatic cancer cell line, Capan1M9, was established previously. After shRNA was stable transducted to knock down CD133 in Capan1M9 cells, gene expression was profiled by DNA microarray. Orthotopic, splenic and intravenous transplantation mouse models were set up to examine the tumorigenesis and metastatic capabilities of these cells. In further experiments, real-time RT-PCR, Western blot and co-immunoprecipitate were conducted to evaluate the interactions of CD133, Slug, N-cadherin, ERK1/2 and SRC.ResultsWe found that CD133+ human pancreatic cancer cells were prone to generating metastatic nodules in in vivo models using immunodeficient mice. In contrast, CD133 knockdown suppressed cancer invasion and metastasis in vivo. Gene profiling analysis suggested that CD133 modulated mesenchymal characteristics including the expression of EMT-related genes, such as Slug and N-cadherin. These genes were down-regulated following CD133 knockdown. Moreover, CD133 expression could be modulated by the extracellular signal-regulated kinase (ERK)1/2 and SRC signaling pathways. The binding of CD133 to ERK1/2 and SRC acts as an indispensable mediator of N-cadherin expression.ConclusionsThese results demonstrate that CD133 plays a critical role in facilitating the EMT regulatory loop, specifically by upregulating N-cadherin expression, leading to the invasion and metastasis of pancreatic cancer cells. Our study provides a novel insight into the function of CD133 in the EMT program and a better understanding of the mechanism underlying the involvement of CD133 in pancreatic cancer metastasis.

【 授权许可】

Unknown   
© Ding et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.