title: Desulfation of cell surface HSPG is an effective strategy for the treatment of gallbladder carcinoma.
abstract: Cell surface heparan sulfate proteoglycan (HSPG) is a group of critical glycoproteins that mediates signal transduction. Sulfated HSPG can mediate the activation of a variety of cell growth factor signal pathway to promote the progression of gallbladder carcinoma (GBC). This study analyzed 527 clinical GBC specimens and confirmed that the HSPG sulfation level was significantly higher in GBC tissues than in gallbladder mucosa (GBM) tissues. The high HSPG sulfation level was closely associated with poor differentiation, local metastasis, and advanced clinical stage of GBC; it was also associated with the shortening of disease-free survival (DFS) and overall survival (OS) and influenced the outcome of chemotherapy or radio-chemotherapy in patients with GBC recurrence. Inhibition of HSPG sulfation on the GBC cell surface using human sulfatase 1 (hSulf-1) significantly reduced the phosphorylation levels of growth factor receptors and signaling protein kinases in GBC cells, decreased cell responses to growth factors, and inhibited cell proliferation and migration abilities. In a nude mouse model with GBC xenografts, we observed that the xenograft tumor growth was suppressed and the phosphorylation levels of signaling proteins were downregulated, together with decreased expression of Ki67 and reduced sensitivity to bFGF (basic fibroblast growth factor) induction after inhibition of HSPG sulfation. Our study demonstrated that a high HSPG sulfation endows GBC with high malignant biological behaviors and a poor prognosis. Desulfation of cell surface HSPG can inhibit the kinase activities of a variety of signaling proteins, hinder the cell response to growth factors, and effectively inhibit the malignant biological behaviors of GBC cells.
authors: Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors: Bin
authors: B
authors: Yi
authors: Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors: Yinghe
authors: Y
authors: Qiu
authors: Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors: Weidan
authors: W
authors: Ji
authors: Department of General Surgery, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200092, China.
authors: Miaoyan
authors: M
authors: Wei
authors: Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors: Chunying
authors: C
authors: Liu
authors: Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors: Zhangxiao
authors: Z
authors: Peng
authors: Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors: Yongjie
authors: Y
authors: Zhang
authors: Department of General Surgery, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200092, China.
authors: Zhiwei
authors: Z
authors: Quan
authors: Department of General Surgery, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200092, China. Electronic address: tangzhaohui001@gmail.com.
authors: Zhaohui
authors: Z
authors: Tang
authors: Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical College, Xuzhou 221002, China. Electronic address: suchangqing@gmail.com.
authors: Changqing
authors: C
authors: Su
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000556:secondary / Q000628:therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018572:Disease-Free Survival; D005260:Female; D005706:Gallbladder Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D019812:Heparan Sulfate Proteoglycans; C470791:SULF1 protein, human; D015238:Sulfotransferases
keywords: Gallbladder carcinoma; Growth factor receptor signal pathway; Heparan sulfate proteoglycan; Sulfation; Target therapy