title: UHRF1 depletion suppresses growth of gallbladder cancer cells through induction of apoptosis and cell cycle arrest.
abstract: Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1), overexpressed in various human malignancies, functions as an important regulator in cell proliferation and epigenetic regulation. Depletion of UHRF1 has shown potential antitumor activities in several types of cancer. However, the role of UHRF1 in gallbladder cancer (GBC) has not been investigated. RT-PCR, western blotting and immunohistochemistry were performed to examine UHRF1 expression at mRNA and protein levels in GBC tissues and cell lines. UHRF1 siRNA and UHRF1 shRNA were used to deplete the expression of UHRF1. The results showed that UHRF1 was overexpressed in GBC and its expression correlated with advanced TNM stage and presence of lymph node metastasis. UHRF1 depletion in GBC-SD and NOZ cells markedly inhibited proliferation, migration in vitro and the ability of these cells to form tumors in vivo. UHRF1 depletion upregulated the expression of PML and triggered extrinsic and intrinsic apoptotic pathways by promoting the expression of FasL/FADD, bax, cytosolic cytochrome c, cleaved caspase-8, -9 and -3 and cleaved PRAP and by suppressing bcl-2 expression in GBC-SD and NOZ cells. In addition, UHRF1 depletion induced cell cycle arrest at G1/S transition by inducing p21 in a p53-independent manner in GBC-SD and NOZ cells. Our findings suggest that UHRF1 is involved in the proliferation and migration of GBC cells and may serve as a biomarker or even a therapeutic target for GBC.
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Mingdi
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Quan
mesh_terms: D017209:Apoptosis / Q000235:genetics; D022762:CCAAT-Enhancer-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D053181:Caspase 8 / Q000096:biosynthesis; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D005706:Gallbladder Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D044767:Ubiquitin-Protein Ligases; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases; D053181:Caspase 8