Wnt signaling and hepatocarcinogenesis: Molecular targets for the development of innovative anticancer drugs

Abstract

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death worldwide. HCC can be cured by radical therapies if early diagnosis is done while the tumor has remained of small size. Unfortunately, diagnosis is commonly late when the tumor has grown and spread. Thus, palliative approaches are usually applied such as transarterial intrahepatic chemoembolization and sorafenib, an anti-angiogenic agent and MAP kinase inhibitor. This latter is the only targeted therapy that has shown significant, although moderate, efficiency in some individuals with advanced HCC. This highlights the need to develop other targeted therapies, and to this goal, to identify more and more pathways as potential targets. The Wnt pathway is a key component of a physiological process involved in embryonic development and tissue homeostasis. Activation of this pathway occurs when a Wnt ligand binds to a Frizzled (FZD) receptor at the cell membrane. Two different Wnt signaling cascades have been identified, called non-canonical and canonical pathways, the latter involving the β-catenin protein. Deregulation of the Wnt pathway is an early event in hepatocarcinogenesis and has been associated with an aggressive HCC phenotype, since it is implicated both in cell survival, proliferation, migration and invasion. Thus, component proteins identified in this pathway are potential candidates of pharmacological intervention. This review focuses on the characteristics and functions of the molecular targets of the Wnt signaling cascade and how they may be manipulated to achieve anti-tumor effects.

Differential expression of glypican-3 (GPC3) in lung squamous cell carcinoma and lung adenocarcinoma and its clinical significance

“…The differential expression of GPC3 can be used to differentiate and diagnose lung squamous cell carcinoma and lung adenocarcinoma. Basic research has indicated that GPC3 regulates the proliferation, differentiation, adhesion, and migration of tumor cells by modulating the insulin-like growth factor and wingless/integrated signaling pathways (Avanesov et al, 2012;Sakane et al, 2012;Pez et al, 2013;Dwivedi et al, 2013;Avanesov and Blair, 2013), thus playing important roles in tumor growth and metastasis. Stronger GPC3 expression has been correlated with increased growth and metastatic potential (Tanaka et al, 2011;Gao and Ho, 2011).…”

Alterations of Wnt/β-catenin signaling pathway in hepatocellular carcinomas associated with hepatitis C virus

“…Involvement of the canonical and non-canonical Wnt pathway in liver oncogenesis has been described by various investigators [59][60][61][62][63][64][65][66][67]. One of the most frequently described mechanisms for activation of the canonical signaling pathway in HCC involves activation of β-catenin through mutations in the CTNNB1 gene.…”

Wnt/?-Catenin Signalling during Liver Metabolism, Chronic Liver Disease and Hepatocarcinogenesis

“…Interestingly, mutations in the β-catenin gene in hepatocellular carcinomas induce overexpression of β-catenin targets such as the glutamine synthetase gene GLUL (66,67), whereas hepatocytes from glutamine synthetase-negative tumours are often H-ras or BRAF mutated and express E-cadherin, reflecting perivenous and periportal profiles, respectively (68). Loss-of-function in APC and Axin is mutually exclusive to CTNNB1 mutations and has been detected in 1-3% and 8-15% of hepatocellular carcinoma cases (for review, see (69)). …”