Down-regulating Glypican-3 Expression: Molecular-targeted Therapy for Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) prognosis is very poor, its early treatment is of the utmost importance. Glypican-3 (GPC-3), a membrane-associated heparan sulfate proteoglycan, plays a crucial role in cell proliferation and metastasis, particularly in progression. GPC-3 mediated oncogenesis involves signaling pathways during the malignant transformation of hepatocyte carcinogenesis, with an increasing expression of GPC-3 observed from non-cancerous- to cancerous-tissues, with brown granule-like staining localized in tumor parts of atypical hyperplasia and HCC formation. GPC-3 expression in HCC tissues or circulating blood was associated with tumor size or HBV infection. Circulation of GPC-3-mRNA was detected in HCC patients with relation to TNM stage, periportal cancerous embolus, and extra-hepatic metastasis. After hepatoma, cells were transfected with shRNA, GPC-3 expression or proliferation was inhibited with promoting apoptosis, cell cycle arrested in G1 phase, alteration of hepatoma cell migration and invasion behaviors with down-regulation of β-catenin, IGF-II, and VEGF, and growth of nude mice xenograft tumors was significantly suppressed with the decreases in β-catenin, p-GSK3β, and cyclinD1 expression, suggesting that GPC-3 not only is a specific biomarker for HCC diagnosis, but also is a valuable molecular-target for HCC gene therapy.

Significance of Glypican-3 (GPC3) Expression in Hepatocellular Cancer Diagnosis

“…HCC early diagnosis and treatment can effectively improve treatment effect and quality of life. Thus, screening molecular markers with high specificity and good sensitivity is of great significance to improve HCC early diagnosis and reduce misdiagnosis [ 15 ]. This study tested cancer tissue GPC3 expression in HCC patients at different clinical stages by immunohistochemistry.…”

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

“…The GPC-3 gene is located on the X human chromosome (Xq26) and it encodes a 70-kDa core protein that can be cleaved by furin to generate a 40 kDa N-terminal-and a 30 kDa C-terminal-protein containing two heparan sulfate glycan chains. Serine 560 is predicted to be a cleavage site in GPC-3, allowing GPC-3 to bind Wnt, Hedgehog (Hh), and fibroblast growth factor-2 through its core protein and/or the HS chains (11,12). GPC-3 contributes to cell migration, invasion, angiogenesis, and apoptosis, possibly through its interactions with the Wnt, Hh, bone morphogenetic protein-7, and insulin-like growth factor (IGF) signaling pathways (13)(14)(15).…”

<p>Preparation and Characterization of Anti-GPC3 Nanobody Against Hepatocellular Carcinoma</p>

“…22 However, objective molecular markers are urgently needed to help standardize the histological diagnosis of early-stage HCC and guide appropriate treatment plans. 23,24 Yukihiro Haruyam et al demonstrated that GPC3 is a prognostic factor and potential immunotherapeutic target for HCC treatment. 8 In contrast, serum alpha-fetoprotein (AFP) has a relatively low sensitivity, and so is of limited value as a serum marker for hepatoblastoma.…”

“…[37][38][39] Although human mAbs against tumor antigens are widely recognized as rational immunotherapeutic tools for cancer treatment, but many mAbs have shown limited efficacy in human clinical trials due to high immunogenicity. 23 Rituximab and daratumumab can trigger cytokine release syndrome and even cause opportunistic virus infection. 40,41 Alternatively, Homayouni et al successfully prepared a functional anti-human TIM-3-specific nanobody with high affinity and anti-proliferative activity on an AML cell line.…”