MicroRNA-33a-mediated downregulation of Pim-3 kinase expression renders human pancreatic cancer cells sensitivity to gemcitabine
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Chen Liang1, Xian-Jun Yu2, Xiao-Zhong Guo3, Meng-Hong Sun4, Zhen Wang1, Yao Song5, Quan-Xing Ni2, Hong-Yu Li3, Naofumi Mukaida5, Ying-Yi Li1,5
1Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
2Department of Pancreas and Hepatobiliary, Pancreatic Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
3Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, Liaoning, China
4Department of Pathology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
5Division of Molecular Bioregulation, Cancer Microenvironment Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
Ying-Yi Li, e-mail: [email protected]
Keywords: miR-33a, serine/threonine kinase, tumor suppressor, chemoresistance, pancreatic cancer
Received: January 09, 2015 Accepted: April 25, 2015 Published: May 08, 2015
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with less than 5% of patients surviving 5 years beyond diagnosis. Systemic therapies, particularly gemcitabine, have a modest clinical benefit, but chemoresistance limits their efficacy. Here, we demonstrate that plasma miR-33a levels positively correlated with miR-33a levels in tumor tissues of patients with PDAC and are a good prognostic indicator of overall survival. Overexpression of miR-33a inhibited tumor cell proliferation and increased the chemosensitivity to gemcitabine both in vitro and in vivo. Moreover, miR-33a targets Pim-3 directly in PDAC. Pim-3 expression was a prognostic indicator related to poor survival in pancreatic cancer patients. Plasma miR-33a levels were significantly lower in pancreatic cancer patients with high Pim-3 protein expression than in healthy controls. Furthermore, overexpression of miR-33a in pancreatic cancer cell lines suppressed Pim-3 expression, leading to downregulation of the AKT/Gsk-3β/β-catenin pathway. Overall, these results indicate that miR-33a functions as a tumor suppressor that downregulates Pim-3 kinase expression to inhibit both pancreatic tumor growth and gemcitabine resistance via the AKT/β-catenin pathway. Hence, detection of plasma miR-33a may be a simple and convenient method of predicting therapeutic responses.
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