title: Evaluation of antiglypican-3 therapy as a promising target for amelioration of hepatic tissue damage in hepatocellular carcinoma.
abstract: In Egypt, hepatocellular carcinoma (HCC) was predicted to continue to rise over the next few decades causing a national problem. Meanwhile, glypican-3 (GPC3), a highly expressed glypican, has emerged as a potential target for HCC immunotherapy. Therefore, we aimed to identify the impact of blocking GPC3 on liver damage in HCC as well as a possible mechanism. Fifty four HCC patients, 20 cirrhotic patients and 10 healthy subjects were recruited. Serum levels of GPC3, sulfatase-2 (SULF-2), heparan sulfate proteoglycan (HSPG), insulin-like growth factor-II (IGF-II) were measured by ELISA. In parallel, HCC was induced in 40 male Sprague-Dawley rats in presence/absence of antiGPC-3. Liver impairment was detected by investigating liver sections stained with hematoxylin/eosin and serum α-fetoprotein (AFP). Liver homogenates of GPC3, SULF-2, and HSPG were measured by ELISA. Gene expression of caspase-3 and IGF-II were assayed by RT-PCR. HCC patients showed significant elevated serum levels of GPC3, IGF-II and SULF-2 accompanied by decreased HSPG. However, treatment of HCC rats with antiGPC-3 significantly reduced serum AFP and showed nearly normal hepatocytes. In addition, antiGPC-3 significantly reduced elevated liver homogenates protein levels of GPC3 and SULF-2 and gene expression of IGF-II and caspase-3. antiGPC-3 restored the reduced hepatic HSPG. antiGPC-3 showed anti-tumor activity as well as hepatoprotective effects. antiGPC-3-chemoprotective effect can be explained by forced reduction of IGF-II expression, restoration of HSPGs, deactivation of SULF-2 and reduction of gene expression of caspase-3. Targeting GPC3 is a promising therapeutic approach for HCC.
authors.affiliation: Dept. of Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt. Electronic address: razaghloul@gmail.com.
authors.forename: Randa A
authors.initials: RA
authors.lastname: Zaghloul
authors.affiliation: Dept. of Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt.
authors.forename: Mamdouh M
authors.initials: MM
authors.lastname: El-Shishtawy
authors.affiliation: Dept. of Microbiology, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt.
authors.forename: Khaled H Abd
authors.initials: KH
authors.lastname: El Galil
authors.affiliation: Oncology Center, University of Mansoura, Mansoura 35516, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Ebrahim
authors.affiliation: Dept. of Internal Medicine, Faculty of Medicine, University of Mansoura, Mansoura 35516, Egypt.
authors.forename: AbdelHamid A
authors.initials: AA
authors.lastname: Metwaly
authors.affiliation: Dept. of Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt; Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia.
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Al-Gayyar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D053673:Glypicans / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C105937:GPC3 protein, human; D053673:Glypicans; C105936:Gpc3 protein, rat
keywords: Caspase-3; Glypican-3 (GPC3); Hepatocellular carcinoma (HCC); Insulin-like growth factor-II (IGF-II); Oxidative stress; Sulfatase-2