title: MicroRNA-34b inhibits pancreatic cancer metastasis through repressing Smad3.
abstract: Pancreatic cancer is characterized by extremely poor prognosis because of early recurrence and metastasis, and increasing evidence supports the critical role of microRNA in cancer progression. Here we identified that microRNA-34b functioned as a tumor-suppressing microRNA by targeting oncogenic Smad3 in pancreatic cancer. As a hypovascular tumor with a potential endoplasmic reticulum stress microenvironment, miR-34b was silenced after ER stress inducer thapsigargin (Tg) treatment and negatively regulated by ER stress chaperone glucose regulated protein 78 (GRP78) in pancreatic cancer cells. In human specimens, we found that miR-34b was down-regulated in pancreatic cancer tissues and low level of miR-34b expression was positively correlated with tumor-node-metastasis (TNM) stage, lymph-node metastasis and overall survival. Functional assays showed that over-expression of miR-34b inhibited pancreatic cancer progression in vitro and in vivo. In addition, Smad3 was demonstrated as a direct target of miR-34b and negatively regulated by miR- 34b at mRNA and protein levels. Luciferase assays confirmed that miR-34b could directly bind to the 3'untranslated region of Smad3. An inverse correlation between miR-34b and Smad3 was observed in 64 pancreatic cancer tissues. Our findings indicate that miR-34b acts as a tumor metastasis suppressor through negatively modulating Smad3, which may provide a potential therapeutic strategy for pancreatic cancer.
authors.affiliation: Department of Pancreatic and Hepatobiliary Surgery, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Cheng
authors.forename: S
authors.initials: S
authors.lastname: Shi
authors.forename: X
authors.initials: X
authors.lastname: Cui
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: P
authors.initials: P
authors.lastname: Cen
authors.forename: X
authors.initials: X
authors.lastname: Cai
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: C
authors.initials: C
authors.lastname: Wu
authors.forename: W
authors.initials: W
authors.lastname: Yao
authors.forename: Y
authors.initials: Y
authors.lastname: Qin
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Long
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.forename: X
authors.initials: X
authors.lastname: Yu
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D018384:Oxidative Stress; D010190:Pancreatic Neoplasms / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D051900:Smad3 Protein / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D017931:DNA Primers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C497790:SMAD3 protein, human; D051900:Smad3 Protein