title: SPOCK1 as a potential cancer prognostic marker promotes the proliferation and metastasis of gallbladder cancer cells by activating the PI3K/AKT pathway.
abstract: BACKGROUND
  Gallbladder cancer (GBC) is a leading cause of cancer-related death worldwide, and its prognosis remains poor, with 5-year survival of approximately 5%. In this study, we analyzed the involvement of a novel proteoglycan, Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1), in the tumor progression and prognosis of human GBC.
  
  
  METHODS
  SPOCK1 expression levels were measured in fresh samples and stored specimens of GBC and adjacent nontumor tissues. The effect of SPOCK1 on cell growth, DNA replication, migration and invasion were explored by Cell Counting Kit-8, colony formation, EdU retention assay, wound healing, and transwell migration assays, flow cytometric analysis, western blotting, and in vivo tumorigenesis and metastasis in nude mice.
  
  
  RESULTS
  SPOCK1 mRNA and protein levels were increased in human GBC tissues compared with those in nontumor tissues. Immunohistochemical analysis indicated that SPOCK1 levels were increased in tumors that became metastatic, compared with those that did not, which was significantly associated with histological differentiation and patients with shorter overall survival periods. Knockdown of SPOCK1 expression by lentivirus-mediated shRNA transduction resulted in significant inhibition of GBC cell growth, colony formation, DNA replication, and invasion in vitro. The knockdown cells also formed smaller xenografted tumors than control GBC cells in nude mice. Overexpression of SPOCK1 had the opposite effects. In addition, SPOCK1 promoted cancer cell migration and epithelial-mesenchymal transition by regulating the expression of relevant genes. We found that activation of the PI3K/Akt pathway was involved in the oncogenic functions of SPOCK1 in GBC.
  
  
  CONCLUSIONS
  SPOCK1 activates PI3K/Akt signaling to block apoptosis and promote proliferation and metastasis by GBC cells in vitro and in vivo. Levels of SPOCK1 increase with the progression of human GBC. SPOCK1 acts as an oncogene and may be a prognostic factor or therapeutic target for patients with GBC.
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. shuyijun19881125@163.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. shuyijun19881125@163.com.
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Shu
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. 535836591@qq.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. 535836591@qq.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Weng
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. yeyuanyuan19891028@126.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. yeyuanyuan19891028@126.com.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Ye
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. kevintony@126.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. kevintony@126.com.
authors.forename: Yun-Ping
authors.initials: YP
authors.lastname: Hu
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. baorunfa163@163.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. baorunfa163@163.com.
authors.forename: Run-Fa
authors.initials: RF
authors.lastname: Bao
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. cycaoyang@163.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. cycaoyang@163.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. xu_anwang@126.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. xu_anwang@126.com.
authors.forename: Xu-An
authors.initials: XA
authors.lastname: Wang
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. fei_zhang_1_2_6@126.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. fei_zhang_1_2_6@126.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. 843178159@qq.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. 843178159@qq.com.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Xiang
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. l.hf.ok@163.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. l.hf.ok@163.com.
authors.forename: Huai-Feng
authors.initials: HF
authors.lastname: Li
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. wuxiangsong_1983@sina.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. wuxiangsong_1983@sina.com.
authors.forename: Xiang-Song
authors.initials: XS
authors.lastname: Wu
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. limaolan6@163.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. limaolan6@163.com.
authors.forename: Mao-Lan
authors.initials: ML
authors.lastname: Li
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. jldaissy@126.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. jldaissy@126.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. wellu@163.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. wellu@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. hanbaosan@126.com.
authors.forename: Bao-San
authors.initials: BS
authors.lastname: Han
authors.affiliation: The Department of General Surgery, First affiliated hospital of Nanchang University, No.17 Yongwaizheng street, Nanchang, 330006, Jiangxi, China. jiezg123@126.com.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Jie
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. liuybphd@126.com.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. liuybphd@126.com.
authors.forename: Ying-Bin
authors.initials: YB
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics; D005260:Female; D005706:Gallbladder Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis; D011509:Proteoglycans / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D011509:Proteoglycans; C504369:SPOCK1 protein, human; D019869:Phosphatidylinositol 3-Kinases