Glypican-3 as an emerging molecular target for hepatocellular carcinoma gene therapy

Abstract

Glypican-3 (GPC-3), a membrane-associated heparan sulfate proteoglycan, plays a crucial role in cell proliferation and metastasis, particularly in hepatocellular carcinoma (HCC) progression, and perhaps is a valuable target for its gene therapy. However, its mechanism remains to be explored. In the present study, the biological behaviors of HCC cells were investigated by interfering GPC-3 gene transcription. After the cells were transfected with specific GPC-3 short hairpin RNA (shRNA), the inhibition of GPC-3 expression was 75.6 % in MHCC-97H or 73.8 % in Huh7 cells at mRNA level; the rates of proliferation and apoptosis were 53.6 and 60.5 % in MHCC-97H or 54.9 and 54.4 % in Huh7 cells, with the cell cycles arrested in the G1 phase; the incidences of cell migration, metastasis, and invasion inhibition were 80.1, 56.4, and 69.1 % in MHCC-97H or 80.9, 59.6, and 58.3 % in Huh7 cells, respectively. The cell biological behaviors were altered by silencing GPC-3 with down-regulation of β-catenin, insulin-like growth factor-II and vascular endothelial growth factor, and Gli1 up-regulation. The cell proliferation was significantly inhibited (up to 95.11 %) by shRNA plus anti-cancer drugs, suggesting that GPC-3 gene should be a potential target for promoting hepatoma cell apoptosis and inhibiting metastasis through the Wnt/β-catenin and Hh singling pathways.

Advances in the study of oncofetal antigen glypican-3 expression in HBV-related hepatocellular carcinoma

“…Besides anti-GPC-3 antibodies, siRNA targeting GPC-3 has also displayed therapeutic efficacy in a model of HCC (54,61). Tumor formation and growth are significantly inhibited by miRNA in a model of HepG2-cell-induced HCC in nude mouse in comparison to the same mice not treated with miRNA ( Figure 2, unpublished data).…”

Glypican‐3: A promising biomarker for hepatocellular carcinoma diagnosis and treatment

“…As noted in Section , miRNAs targeting GPC3 have exhibited antitumor efficacy in HCC xenograft models. RNA interference by using a GPC3 shRNAs inhibited the proliferative and invasive ability of HCC cells and HCC xenograft tumors, induced cell‐cycle arrest in the G1 phase and apoptosis, and altered biological responses (including downregulation of β‐catenin and vascular endothelial growth factor, and upregulation of Gli1) . Moreover, GPC3 knockdown by using siRNAs inhibited HCC cell proliferation through YAP downregulation, induced apoptosis, suppressed HCC cell growth through TGF‐β2 upregulation, and downregulated cell invasion and migration probably through EMT inactivation .…”

Expression of oncofetal antigen glypican-3 associates significantly with poor prognosis in HBV-related hepatocellular carcinoma

“…Activation of some key signal molecules in inflammation-related liver diseases regulates the expression of inflammation response- or cancer related genes [22, 23]. GPC-3 gene is located in upstream of the Wnt signal pathway that is involved in the initiation, generation, and tumor development, and up-regulated in HBV-related liver malignancies [19]. It promotes the growth of HCC by stimulating canonical Wnt signaling because the structural requirements for GPC3 activity are cell type specific, and its core protein is processed by a furin-like convertase, In this study, the expression and cellular distribution of hepatic GPC-3 in HCC were investigated to assess its prognostic value of HCC.…”

“…There were strong brown staining particles in the cytoplasm and membrane or a few nuclei with high GPC-3/β-actin ratio in HCC, light staining in the para-cancerous-, and none in the non-cancerous tissues. The significantly different of GPC-3 incidence or intensity was found between HCC and their surrounding- or distal cancerous-tissues, indicating that GPC-3 expression could associate significantly with HCC progression [19]. …”

“…GPC-3 as an oncofetal antigen was in favors of cell proliferation and metastasis [17, 18] and could be an emerging molecular target for HCC gene therapy. However, the value of hepatic GPC-3 as a prognostic biomarker for HCC remains to be clarified [19]. The objectives of this present study were to investigate the hepatic GPC-3 expression and cellular distribution in HCC and their matched-surrounding tissues by the array technology with immunohistochemistry and analyze the clinical value of GPC-3 as a novel molecular marker for HBV-related HCC patients' prognosis.…”