Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells

Kim, Miran; Lee, Han Chu; Tsedensodnom, Orkhontuya; Hartley, Rochelle; Lim, Young‐Suk; Yu, Eunsil; Merle, Philippe; Wands, Jack R.

doi:10.1016/j.jhep.2007.12.020

Cited by 171 publications

(186 citation statements)

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“…The noncanonical PKC and JNK pathways have been clearly shown as potentially activated by some FZD family members as FZD7, whereas it remains ambiguous for FZD3 and FZD6 (He et al, 1998;Winklbauer et al, 2001;Kinoshita et al, 2003;Merle et al, 2004;Katoh, 2007;Katoh and Katoh, 2007b). We have previously reported that the FZD7-mediated signalling was able to control the cancerous phenotype of human HCC cell lines through b-catenin protein regulation, and that one of the Wnt ligand candidate activators is WNT3 (Merle et al, 2004(Merle et al, , 2005Kim et al, 2008). Nothing is clear about the functional interaction between FZD7 and WNT4 or WNT5A.…”

Section: Discussionmentioning

confidence: 99%

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Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma

et al. 2008

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Dysregulation of growth factors and their receptors is central to human hepatocellular carcinoma (HCC). We previously demonstrated that the Frizzled-7 membrane receptor mediating the Wnt signalling can activate the b-catenin pathway and promotes malignancy in human hepatitis B virus-related HCCs. Expression patterns of all the 10 Frizzled receptors, and their extracellular soluble autoparacrine regulators (19 Wnt activators and 4 sFRP inhibitors) were assessed by real-time RT -PCR in 62 human HCC of different etiologies and their matched peritumorous areas. Immunostaining was performed to localise Frizzled on cell types in liver tissues. Regulation of three known Frizzled-dependent pathways (b-catenin, protein kinase C, and C-Jun NH 2 -terminal kinase) was measured in tissues by western blot. We found that eight Frizzled-potentially activating events were pleiotropically dysregulated in 95% HCC and 68% peritumours as compared to normal livers (upregulations of Frizzled-3/6/7 and Wnt3/4/5a, or downregulation of sFRP1/5), accumulating gradually with severity of fibrosis in peritumours and loss of differentiation status in tumours. The hepatocytes supported the Wnt/Frizzled signalling since specifically overexpressing Frizzled receptors in liver tissues. Dysregulation of the eight Frizzled-potentially activating events was associated with differential activation of the three known Frizzled-dependent pathways. This study provides an extensive analysis of the Wnt/Frizzled receptor elements and reveals that the dysregulation may be one of the most common and earliest events described thus far during hepatocarcinogenesis.

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Section: Discussionmentioning

confidence: 99%

“…Additionally, we have shown that FZD7 can be activated in vitro by binding of the WNT3 ligand (Kim et al, 2008). In this study, the expression patterns of all 19 WNT, 10 FZD, two LRP, and four sFRP genes have been determined in HCCs and in their matched surrounding precancerous peritumorous areas, by comparison to normal liver (NL) tissues.…”

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confidence: 97%

Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma

et al. 2008

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“…Furthermore, three other Wnt genes (Wnt3, Wnt4 and Wnt5A), and three FZD genes (FZD3, FZD6 and FZD7) are also upregulated in HCC tissues and preneoplastic peritumoural tissues as compared with normal liver tissues, suggesting that their overexpression may be an early event in hepatocarcinogenesis. However, only the overexpression of FZD7 has been associated with nuclear and/or cytoplasmic accumulation of β-catenin in HCC [70][71][72] .…”

Section: Wnt and Fzdmentioning

confidence: 98%

“…The TCF/LEF family has several spliced forms with unknown functional significance and it is suggested that they may activate preferential genes [86] . In HCC, mutations of TCF-4 are rare with 315 August 10, 2011|Volume 2|Issue 8| WJCO|www.wjgnet.com [70][71][72] phospho-GSK3β High 52 IHC [73] Axin1 Low 67 IHC [76] Dvl High 71 Western blotting [82] Prickle-1 Low 55 PCR [82] HDPR1 Low 58 PCR [83] PIN1 High 53 Western blotting [65] TCF-4 High 91 PCR [87] LEF-1 High 52 IHC [88] CDH17 High 72 IHC [90] CDH17: Cadherin-17; Dvl: Dishevelled; FZD: Frizzled; phospho-GSK3β: Phosphorylated glycogen synthase kinase 3β; HDPR1: Human homologue of Dapper; IHC: Immunohistochemistry; LEF: Lymphoid enhancer factor; PCR: Polymerase chain reaction; PIN1: Peptidyl-prolyl cis/trans isomerase; TCF: T-cell factor.…”

Section: Tcf/lefmentioning

confidence: 99%

Dickkopfs and Wnt/β-catenin signalling in liver cancer

Fatima¹

2011

WJCO

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Liver cancer is the fifth and seventh most common cause of cancer in men and women, respectively. Wnt/β-catenin signalling has emerged as a critical player in both the development of normal liver as well as an oncogenic driver in hepatocellular carcinoma (HCC). Based on the current understanding, this article summarizes the possible mechanisms for the aberrant activation of this pathway with specific focus on HCC. Furthermore, we will discuss the role of dickkopfs (DKKs) in regulating Wnt/β-catenin signalling, which is poorly understood and understudied. DKKs are a family of secreted proteins that comprise at least four members, namely DKK1-DKK4, which act as inhibitors of Wnt/β-catenin signalling. Nevertheless, not all members antagonize Wnt/β-catenin signalling. Their functional significance in hepatocarcinogenesis remains to be further characterized for which these studies should provide new insights into the regulatory role of DKKs in Wnt/β-catenin signalling in hepatic carcinogenesis. Because of the important oncogenic roles, there are an increasing number of therapeutic molecules targeting β-catenin and the Wnt/ β-catenin pathway for potential therapy of HCC. hepatocellular carcinoma anD the unmet meDical neeDSLiver cancer ranks the fifth most common cancer in men and the second leading cause of cancer-related death. In women, it is the seventh most frequent cancer and sixth leading cause of cancer death [1] . Hepatocellular carcinoma (HCC) is the most common primary malignancy of liver. Men are three times more likely to develop HCC than women and the incidence increases with age [2] . HCC is prevalent in Asia and Africa, but recently it is on the rise in the Western world due to an increase in hepatitis C virus (HCV) infection [3] . Risk factors for HCC include chronic hepatitis B virus (HBV) and HCV infections, cirrhosis, chronic alcohol abuse, aflatoxin ingestion, non-alcoholic steatohepatitis and other metabolic liver diseases [4,5] . Much of HCC occurs in the background of cirrhosis. About 80%-90% of patients with cirrhosis go on to develop HCC eventually and the remaining 10%-20% of cases develop HCC without cirrhosis. Furthermore, HBV and HCV infections increase the risk of developing cirrhosis and later HCC. Among the HCC

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“…The Wnt/betacatenin signaling pathway regulates various aspects of development and plays important role in tumor formation in multiple tissues and organs (such as the colon, breast, ovarian, liver, etc.) (Lee et al, 2006;Kim et al, 2008;Yuzugullu et al, 2009). …”

Section: Introductionmentioning

confidence: 99%