4.8 Article

Pancreatic RECK inactivation promotes cancer formation, transition, and metastasis

期刊

JOURNAL OF CLINICAL INVESTIGATION
卷 133, 期 18, 页码 -

出版社

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI161847

关键词

-

向作者/读者索取更多资源

RECK downregulation promotes the development and metastasis of pancreatic ductal adenocarcinoma (PDAC) by inducing epithelial-mesenchymal transition (EMT) and inflammatory cancer-associated fibroblast-like cells. Reexpression of RECK reduces metastasis and changes the tumor phenotype from mesenchymal to epithelial, suggesting that RECK could be an important therapeutic target for human PDAC.
RECK is downregulated in various human cancers; however, how RECK inactivation affects carcinogenesis remains unclear. We addressed this issue in a pancreatic ductal adenocarcinoma (PDAC) mouse model and found that pancreatic Reck deletion dramatically augmented the spontaneous development of PDAC with a mesenchymal phenotype, which was accompanied by increased liver metastases and decreased survival. Lineage tracing revealed that pancreatic Reck deletion induced epithelialmesenchymal transition (EMT) in PDAC cells, giving rise to inflammatory cancer-associated fibroblast-like cells in mice. Splenic transplantation of Reck-null PDAC cells resulted in numerous liver metastases with a mesenchymal phenotype, whereas reexpression of RECK markedly reduced metastases and changed the PDAC tumor phenotype into an epithelial one. Consistently, low RECK expression correlated with low E-cadherin expression, poor differentiation, metastasis, and poor prognosis in human PDAC. RECK reexpression in the PDAC cells was found to downregulate MMP2 and MMP3, with a concomitant increase in E-cadherin and decrease in EMT-promoting transcription factors. An MMP inhibitor recapitulated the effects of RECK on the expression of E-cadherin and EMT-promoting transcription factors and invasive activity. These results establish the authenticity of RECK as a pancreatic tumor suppressor, provide insights into its underlying mechanisms, and support the idea that RECK could be an important therapeutic effector against human PDAC.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.8
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据