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Oncotarget. 2015 Jun 10;6(16):14440-55.

MicroRNA-33a-mediated downregulation of Pim-3 kinase expression renders human pancreatic cancer cells sensitivity to gemcitabine.

Author information

1
Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
2
Department of Pancreas and Hepatobiliary, Pancreatic Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
3
Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, Liaoning, China.
4
Department of Pathology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
5
Division of Molecular Bioregulation, Cancer Microenvironment Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.

Abstract

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.

KEYWORDS:

chemoresistance; miR-33a; pancreatic cancer; serine/threonine kinase; tumor suppressor

PMID:
25971209
PMCID:
PMC4546478
DOI:
10.18632/oncotarget.3885
[Indexed for MEDLINE]
Free PMC Article

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