Wnt/frizzled signaling in hepatocellular carcinoma

Hc, Lee; Kim, Mi‐Hyun; Wands,

doi:10.2741/1933

Cited by 140 publications

(118 citation statements)

References 121 publications

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“…Dysregulation of the Wnt signaling pathway is a key molecular lesion in liver cancer (36)(37)(38). More than 60% of liver tumors exhibit accumulation of β-catenin, a hallmark of activated Wnt signaling.…”

Section: Discussionmentioning

confidence: 99%

A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer

O’Donnell

Keng

York

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The Sleeping Beauty (SB) transposon mutagenesis system is a powerful tool that facilitates the discovery of mutations that accelerate tumorigenesis. In this study, we sought to identify mutations that cooperate with MYC, one of the most commonly dysregulated genes in human malignancy. We performed a forward genetic screen with a mouse model of MYC-induced liver cancer using SBmediated mutagenesis. We sequenced insertions in 63 liver tumor nodules and identified at least 16 genes/loci that contribute to accelerated tumor development. RNAi-mediated knockdown in a liver progenitor cell line further validate three of these genes, Ncoa2/ Src-2, Zfx, and Dtnb, as tumor suppressors in liver cancer. Moreover, deletion of Ncoa2/Src-2 in mice predisposes to diethylnitrosamineinduced liver tumorigenesis. These findings reveal genes and pathways that functionally restrain MYC-mediated liver tumorigenesis and therefore may provide targets for cancer therapy. T ransposable elements (TEs) are powerful genetic tools that are widely used in insertional mutagenesis screens because of the facile identification of transposon-induced mutations. The application of transposon-based approaches to cancer gene identification provides opportunities to study the consequences of specific mutations in the context of tumor cell initiation, progression, and maintenance in well-defined, genetically engineered mouse models. Sleeping Beauty (SB), a member of the Tc1/mariner superfamily of DNA transposons, is highly active in mammalian cells (1). A growing body of evidence has demonstrated that SB is an efficient tool for cancer gene discovery when used in forward genetic screens in mice (2, 3).The SB system is based on the use of two transgenic mouse lines, one harboring a transposase and the other with a concatemerized mutagenic transposon containing sequences that can disrupt gene function through either gain-of-function or loss-offunction mechanisms. The transposase binds to the transposon ends and catalyzes its mobilization to new sites. The effect of ubiquitous transposition in mice is the development of T-cell leukemia and brain tumors (3, 4). In contrast, restricted expression of SB transposase accelerates fibrosarcoma development in p19 Arf −/− mice (2).Recently, this approach has been modified through the conditional activation of the SB transposase in specific tissues using Cre/LoxP technology (5, 6). In one of these studies, an SB screen identified 19 genes that accelerate liver cancer induced by expression of a dominant-negative Trp53 transgene. However, the SB system has not been used previously to identify genes that cooperate with oncogenes that initiate liver tumorigenesis.Hepatocellular carcinoma (HCC) is the fifth most common solid tumor worldwide and is the third leading cause of death from cancer (7,8). In the majority of cases, it occurs in a setting of chronic inflammation or cirrhosis. Although numerous genomic alterations have been documented in liver cancer, the key genetic alterations that drive hepatocellular transforma...

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Section: Discussionmentioning

confidence: 99%

A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer

O’Donnell

Keng

York

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Activation of the canonical Wnt pathway has been found to be one of the most frequent events associated with the malignant transformation of liver cells [49][50][51][52]. Because GPC3 promotes HCC growth by stimulating canonical Wnt signaling, treatments that target this pathway downstream of this glypican could offer alternative possibilities for blocking its pro-tumorigenic activity.…”

Section: Potential Association With Wnt/3-catenin Therapeuticsmentioning

confidence: 99%

Therapeutic Potential of Targeting Glypican-3 in Hepatocellular Carcinoma

Allegretta¹,

Filmus²

2011

ACAMC

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Glypican-3 (GPC3) is a developmentally-regulated oncofetal protein that has been established as a clinically-relevant biomarker for early hepatocellular carcinoma (HCC). It is one of the first transcripts to appear during malignant hepatocyte transformation, and is expressed at the protein level in approximately half of high-grade dysplastic macronodules in cirrhotic liver. Several studies show it is expressed in most (75 to 100%) of HCCs confirmed by histopathology. The protein is anchored to the hepatocyte membrane by a glycosyl-phosphatidylinositol (GPI) anchor and shows consistent membrane immunostaining pattern, making it a viable target for immunotherapeutic approaches. Targeting GPC3 for therapeutic intervention is a promising approach for the clinical management of HCC and selected other tumors that express the marker.

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“…Frequent mutations of the β-catenin gene were found in chemically induced colon tumors in both rat and mouse carcinogenesis models (Dashwood et al, 1998;Takahashi et al, 1998;Suzui et al, 1999), suggesting that the APC-β-catenin pathway plays an important role in the development of colon carcinogenesis in rodents, as seen in humans. Recent reports shown that activation of Wnt/β-catenin signaling is important for both initiation and progression of cancers of different tissues/organs, including liver (Lee et al, 2006;Ashokkumar and Sudhandiran, 2011), thus, Wnt/β-catenin signaling pathway is becoming a promising target for chemoprevention and chemotherapy in CRC (Herbst and Kolligs, 2007;Luo et al, 2007;Ashokkumar and Sudhandiran, 2011).…”

Section: 2201 Potential Targets For Prevention Of Colorectal Cancer:mentioning

confidence: 99%

Potential Targets for Prevention of Colorectal Cancer: a Focus on PI3K/Akt/mTOR and Wnt Pathways

Pandurangan¹

2013

Asian Pacific Journal of Cancer Prevention

172

146

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Colorectal cancer (CRC) is one of the most common cancers in many parts of the world. Its development is a multi-step process involving three distinct stages, initiation that alters the molecular message of a normal cell, followed by promotion and progression that ultimately generates a phenotypically altered transformed malignant cell. Reports have suggested an association of the phosphoinositide-3-kinase (PI3K)/Akt pathway with colon tumorigenesis. Activation of Akt signaling and impaired expression of phosphatase and tensin homolog (PTEN) (a negative regulator of Akt) has been reported in 60-70% of human colon cancers and inhibitors of PI3K/Akt signaling have been suggested as potential therapeutic agents. Around 80% of human colon tumors possess mutations in the APC gene and half of the remainder feature β-catenin gene mutations which affect downstream signaling of the PI3K/Akt pathway. In recent years, there has been a great focus in targeting these signaling pathways, with natural and synthetic drugs reducing the tumor burden in different experiment models. In this review we survey the role of PI3K/Akt/mTOR and Wnt signaling in CRC.

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Wnt/frizzled signaling in hepatocellular carcinoma

Cited by 140 publications

References 121 publications

A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer

A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer

Therapeutic Potential of Targeting Glypican-3 in Hepatocellular Carcinoma

Potential Targets for Prevention of Colorectal Cancer: a Focus on PI3K/Akt/mTOR and Wnt Pathways

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