Oncotarget

Research Papers:

MicroRNA-323-3p inhibits cell invasion and metastasis in pancreatic ductal adenocarcinoma via direct suppression of SMAD2 and SMAD3

Chunyou Wang, Pian Liu, Heshui Wu, Pengfei Cui, Yongfeng Li, Yao Liu, Zhiqiang Liu and Shanmiao Gou _

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Oncotarget. 2016; 7:14912-14924. https://doi.org/10.18632/oncotarget.7482

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Abstract

Chunyou Wang1,*, Pian Liu2,*, Heshui Wu1, Pengfei Cui1, Yongfeng Li1, Yao Liu3, Zhiqiang Liu1, Shanmiao Gou1

1Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People’s Republic of China

2Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People’s Republic of China

3Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People’s Republic of China

*These authors have contributed equally to this work

Correspondence to:

Shanmiao Gou, e-mail: [email protected]

Keywords: miR-323-3p, pancreatic ductal adenocarcinoma, SMAD2, SMAD3

Received: August 14, 2015    Accepted: January 29, 2016    Published: February 18, 2016

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC), which accounts for 96% of all pancreatic cancer cases, is characterized by rapid progression, invasion and metastasis. Transforming growth factor-beta (TGF-β) signaling is an essential pathway in metastatic progression and microRNAs (miRNA) play central roles in the regulation of various biological and pathologic processes including cancer metastasis. However, the molecular mechanisms involved in regulation of miRNAs and activation of TGF-β signaling in PDAC remain to be established. The results of this study suggested that miR-323-3p expression in PDAC tissues and cell lines was significantly decreased compared to levels in normal pancreatic tissues and primary cultured pancreatic duct epithelial cells. Further investigation revealed that miR-323-3p directly targeted and suppressed SMAD2 and SMAD3, both key components in TGF-β signaling. Lower levels of miR-323-3p predicted poorer prognosis in patients with PDAC. Ectopic overexpression of miR-323-3p significantly inhibited, while silencing of miR-323-3p increased the migration and invasion abilities of PDAC cells in vitro. Moreover, using an in vivo mouse model, we demonstrated that overexpressing of miR-323-3p significantly reduced, while knockdown of miR-323-3p enhanced lung metastatic colonization of PANC-1 cells. Furthermore, miR-323-3p-induced TGF-b signaling inhibition and cell motility suppression were partially rescued by overexpressing of Smad2 and Smad3 in PDAC cells. Our findings suggest that re-expression of miR-323-3p might offer a novel therapeutic target against metastasis in patients with PDAC.


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