Evaluation of antiglypican-3 therapy as a promising target for amelioration of hepatic tissue damage in hepatocellular carcinoma

• Published in: European journal of pharmacology Vol. 746; pp. 353 - 362
• Main Authors: Zaghloul, Randa A., El-Shishtawy, Mamdouh M., El Galil, Khaled H. Abd, Ebrahim, Mohamed A., Metwaly, AbdelHamid A., Al-Gayyar, Mohammed M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.01.2015
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents - therapeutic use; Carcinoma, Hepatocellular - chemically induced; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Caspase-3; Female; Glypican-3 (GPC3); Glypicans - antagonists & inhibitors; Glypicans - blood; Glypicans - metabolism; Hepatocellular carcinoma (HCC); Humans; Insulin-like growth factor-II (IGF-II); Liver - drug effects; Liver - metabolism; Liver - pathology; Liver Neoplasms - chemically induced; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Oxidative stress; Random Allocation; Rats, Sprague-Dawley; Sulfatase-2; Survival Analysis; Up-Regulation - drug effects; Sulfatase-2; Oxidative stress; IHC; ALT; AFP; HS; MDA; Caspase-3; Ct; RT-PCR; GPC3; cDNA; Glypican-3 (GPC3); GSH; HBV; Hepatocellular carcinoma (HCC); HCC; SOD; I.P; HSPGs; ECM; rpm; S.E.M; AntiGPC-3; SULF-2; Insulin-like growth factor-II (IGF-II); HCV; GAPDH; ELISA; H/E; IGF-II
• ISSN: 0014-2999; 1879-0712; 1879-0712
• DOI: 10.1016/j.ejphar.2014.11.008

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. [Display omitted]