title: MicroRNA-33a-mediated downregulation of Pim-3 kinase expression renders human pancreatic cancer cells sensitivity to gemcitabine.
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.
authors.affiliation: Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Liang
authors.affiliation: Department of Pancreas and Hepatobiliary, Pancreatic Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xian-Jun
authors.initials: XJ
authors.lastname: Yu
authors.affiliation: Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, Liaoning, China.
authors.forename: Xiao-Zhong
authors.initials: XZ
authors.lastname: Guo
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Meng-Hong
authors.initials: MH
authors.lastname: Sun
authors.affiliation: Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Division of Molecular Bioregulation, Cancer Microenvironment Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Yao
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Pancreas and Hepatobiliary, Pancreatic Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Quan-Xing
authors.initials: QX
authors.lastname: Ni
authors.affiliation: Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, Liaoning, China.
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Li
authors.affiliation: Division of Molecular Bioregulation, Cancer Microenvironment Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
authors.affiliation: Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.|Division of Molecular Bioregulation, Cancer Microenvironment Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Li
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation; D016147:Genes, Tumor Suppressor / Q000187:drug effects*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D003841:Deoxycytidine; C499249:PIM3 protein, human; D017346:Protein Serine-Threonine Kinases; D000093542:Gemcitabine
keywords: chemoresistance; miR-33a; pancreatic cancer; serine/threonine kinase; tumor suppressor