Epidermal Growth Factor Receptor: A Novel Target of the Wnt/β-Catenin Pathway in Liver

Tan, Xinping; Apte, Udayan; Micsenyi, Amanda; Kotsagrelos, Emorphia; Luo, Jianhua; Ranganathan, Sarangarajan; Monga, Dulabh; Bell, Aaron; Michalopoulos, George K.; Monga, Satdarshan P.

doi:10.1053/j.gastro.2005.04.013

Cited by 207 publications

(168 citation statements)

References 68 publications

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“…In addition, co-activation of EGFR and β-catenin is commonly seen in patients with HCC (Llovet et al, 2008). Some reports have demonstrated that Wnt/β-catenin activation could induce the EGFR activation in HCC (Tan et al, 2005). Interestingly, in the present study, we showed that EGFR activation induced β-catenin activation in HCC cell lines, highlighting the crosstalk between EGFR and Wnt pathways, which could be important for HCC tumorigenesis, progression and metastasis.…”

Section: Discussionsupporting

confidence: 59%

PKM2 Regulates Hepatocellular Carcinoma Cell Epithelial-mesenchymal Transition and Migration upon EGFR Activation

Fan

Shen²,

Li³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Pyruvate kinase isozyme type M2 (PKM2) was first found in hepatocellular carcinoma (HCC), and its expression has been thought to correlate with prognosis. A large number of studies have demonstrated that epithelial-mesenchymal transition (EMT) is a crucial event in hepatocellular carcinoma (HCC) and associated metastasis, resulting in enhanced malignancy of HCC. However, the roles of PKM2 in HCC EMT and metastasis remain largely unknown. The present study aimed to determine the effects of PKM2 in EGF-induced HCC EMT and elucidate the molecular mechanisms in vitro. Our results showed that EGF promoted EMT in HCC cell lines as evidenced by altered morphology, expression of EMT-associated markers, and enhanced invasion capacity. Furthermore, the present study also revealed that nuclear translocation of PKM2, which is regulated by the ERK pathway, regulated β-catenin-TCF/LEF-1 transcriptional activity and associated EMT in HCC cell lines. These discoveries provide evidence of novel roles of PKM2 in the progression of HCC and potential therapeutic target for advanced cases.

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Section: Discussionsupporting

confidence: 59%

PKM2 Regulates Hepatocellular Carcinoma Cell Epithelial-mesenchymal Transition and Migration upon EGFR Activation

Fan

Shen²,

Li³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…Activation of the epidermal growth factor receptor has likewise recently been shown to activate h-catenin expression in liver carcinomas (50). It is therefore tempting to also speculate that the epidermal growth factor receptor might be a possible target for (-)-agelastatin A.…”

Section: Discussionmentioning

confidence: 98%

“…It potently inhibits the growth of murine and human cancer cell lines at low drug concentrations (11 -15) by mechanisms that have yet to be fully delineated. In this regard, (-)-agelastatin A potently retards the growth of a range of human tumor cell lines that include KB nasopharyngeal cancer cells (IC 50 , 0.075 Ag/mL), RT112/84 bladder carcinoma cells, SK-MEL-5 melanoma cells, HCT-116 colon carcinoma cells, and MDA-MB-435s breast cancer cells (15). In the latter four cell lines, (-)-agelastatin A is between 3 and 16 times more potent as an anticancer drug than the frontline chemotherapeutic agent cisplatin (15).…”

Section: Introductionmentioning

confidence: 99%

Agelastatin A: a novel inhibitor of osteopontin-mediated adhesion, invasion, and colony formation

Mason

McFarlane

Johnston

et al. 2008

Molecular Cancer Therapeutics

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Effective inhibitors of osteopontin (OPN) -mediated neoplastic transformation and metastasis are still lacking. (-)-Agelastatin A is a naturally occurring oroidin alkaloid with powerful antitumor effects that, in many cases, are superior to cisplatin in vitro . In this regard, past comparative assaying of the two agents against a range of human tumor cell lines has revealed that typically (-)-agelastatin A is 1.5 to 16 times more potent than cisplatin at inhibiting cell growth, its effects being most pronounced against human bladder, skin, colon, and breast carcinomas. In this study, we have investigated the effects of (-)-agelastatin A on OPN-mediated malignant transformation using mammary epithelial cell lines. Treatment with (-)-agelastatin A inhibited OPN protein expression and enhanced expression of the cellular OPN inhibitor, Tcf-4. (-)-Agelastatin A treatment also reduced B-catenin protein expression and reduced anchorage-independent growth, adhesion, and invasion in R37 OPN pBK-CMV and C9 cell lines. Similar effects were observed in MDA-MB-231 and MDA-MB-435s human breast cancer cell lines exposed to (-)-agelastatin A. Suppression of Tcf-4 by RNA interference (short interfering RNA) induced malignant/invasive transformation in parental benign Rama 37 cells; significantly, these events were reversed by treatment with (-)-agelastatin A. Our study reveals, for the very first time, that (-)-agelastatin A down-regulates B-catenin expression while simultaneously up-regulating Tcf-4 and that these combined effects cause repression of OPN and inhibition of OPN-mediated malignant cell invasion, adhesion, and colony formation in vitro. We have also shown that (-)-agelastatin A inhibits cancer cell proliferation by causing cells to accumulate in the G 2 phase of cell cycle.

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“…Recently published data on transgenic mice overexpressing b-catenin strengthen this assumption, as increased b-catenin expression leads to elevated EGFR levels in hepatocytes. Moreover, immunohistological analyses show a high correlation between the expression of nuclear/cytoplasmic b-catenin and EGFR in most hepatoblastomas (Tan et al, 2005).…”

Section: Cross-talk With Protumorigenic Factorsmentioning

confidence: 97%

Dysregulation of growth factor signaling in human hepatocellular carcinoma

2006

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Epidermal Growth Factor Receptor: A Novel Target of the Wnt/β-Catenin Pathway in Liver

Abstract: Background & Aims-Wnt/β-catenin activation is observed in normal liver development, regeneration, and liver cancer. Our aim was to elucidate the regulation and mechanism of this pathway in liver.

Cited by 207 publications

References 68 publications

PKM2 Regulates Hepatocellular Carcinoma Cell Epithelial-mesenchymal Transition and Migration upon EGFR Activation

PKM2 Regulates Hepatocellular Carcinoma Cell Epithelial-mesenchymal Transition and Migration upon EGFR Activation

Agelastatin A: a novel inhibitor of osteopontin-mediated adhesion, invasion, and colony formation

Dysregulation of growth factor signaling in human hepatocellular carcinoma

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