Overexpression of extracellular signal‐regulated protein kinase and its correlation with proliferation in human hepatocellular carcinoma

Tsuboi, Yasunori; Ichida, Takafumi; Sugitani, Soichi; Genda, Takuya; Inayoshi, Jun; Takamura, Masaaki; Matsuda, Yasunobu; Nomoto, Minoru; Aoyagi, Yoshinobu

doi:10.1111/j.1478-3231.2004.0940.x

Cited by 69 publications

(56 citation statements)

References 22 publications

(27 reference statements)

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“…Inhibition of ERK by dominant-negative ERK or antisense nucleotides of ERK exhibits the suppression of cell growth (Bottazzi et al, 1999). Previous studies have shown that overexpression of ERK in HCC is correlated with its proliferative activity (Ito et al, 1998;Tsuboi et al, 2004). The kinase activity of ERK is fully activated through the phosphorylation of threonine (Thr 202) and tyrosine (Tyr 204) of ERK by MAP kinase kinase (MEK), which is activated by Raf.…”

Section: Discussionmentioning

confidence: 99%

“…In human hepatocellular carcinoma (HCC), proliferative activity is higher even in precancerous lesions, such as adenomatous hyperplasia, than in the adjacent nontumorous liver tissue. Previous studies have shown that various growth factors enhance HCC cell proliferation through the activation of the Ras/Raf-1/ERK pathway and aberrant activation of this pathway is frequently observed in human HCC (Schmidt et al, 1997;Ito et al, 1998;Tsuboi et al, 2004), although most HCC tumors lack oncogenic Ras mutation. In addition, high tumor proliferation induced by ERK activation is closely linked to resistance against any type of therapy, including irradiation therapy and chemotherapy, resulting in shorter survival times for patients.…”

Section: Introductionmentioning

confidence: 99%

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Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

et al. 2006

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Aberrant activation of the Ras/Raf-1/extracellular-regulated kinase (ERK) pathway has been shown to be involved in the progression of human hepatocellular carcinoma (HCC). However, the mechanism of dysregulation of ERK activation is poorly understood. Recently, we identified Sprouty-related protein with Ena/vasodilator-stimulated phosphoprotein homology-1 domain (Spred) as a physiological inhibitor of the Ras/Raf-1/ ERK pathway. In this study, we found that the expression levels of Spred-1 and -2 in human HCC tissue were frequently decreased, comparing with those in adjacent non-tumorous tissue. Moreover, Spred expression levels in HCC tissue were inversely correlated with the incidence of tumor invasion and metastasis. Forced expression of Spred-1 inhibited HCC cell proliferation in vitro and in vivo, which was associated with reduced ERK activation. Spred-1 overexpression also reduced the secretion of matrix metalloproteinase-9 (MMP-9) and MMP-2, which play important roles in tumor invasion and metastasis. In addition, Spred-1 inhibited growth factor-mediated HCC cell motility. These data indicate that the reduction of Spred expression in HCC is one of the causes of the acquisition of malignant features. Thus, Spred could be not only a novel prognostic factor but also a new therapeutic target for human HCC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

et al. 2006

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“…In the majority of human HCCs, the Erk/MAPK pathway has been described to be activated (Nijhara et al, 2001;Tsuboi et al, 2004). Once activated, TGF-b is supposed to switch to a tumorprogressive function in (pre)-cancerous hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

PDGF essentially links TGF-β signaling to nuclear β-catenin accumulation in hepatocellular carcinoma progression

et al. 2006

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The cooperation of Ras -extracellular signal-regulated kinase/mitogen-activated protein kinase and transforming growth factor (TGF)-b signaling provokes an epithelial to mesenchymal transition (EMT) of differentiated p19 ARF null hepatocytes, which is accompanied by a shift in malignancy and gain of metastatic properties. Upon EMT, TGF-b induces the secretion and autocrine regulation of platelet-derived growth factor (PDGF) by upregulation of PDGF-A and both PDGF receptors. Here, we demonstrate by loss-of-function analyses that PDGF provides adhesive and migratory properties in vitro as well as proliferative stimuli during tumor formation. PDGF signaling resulted in the activation of phosphatidylinositol-3 kinase, and furthermore associated with nuclear b-catenin accumulation upon EMT. Hepatocytes expressing constitutively active b-catenin or its negative regulator Axin were employed to study the impact of nuclear b-catenin. Unexpectedly, active b-catenin failed to accelerate proliferation during tumor formation, but in contrast, correlated with growth arrest. Nuclear localization of b-catenin was accompanied by strong expression of the Cdk inhibitor p16INK4A and the concomitant induction of the b-catenin target genes cyclin D1 and c-myc. In addition, active b-catenin revealed protection of malignant hepatocytes against anoikis, which provides a prerequisite for the dissemination of carcinoma. From these data, we conclude that TGF-b acts tumor progressive by induction of PDGF signaling and subsequent activation of bcatenin, which endows a subpopulation of neoplastic hepatocytes with features of cancer stem cells.

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“…In previous studies, various growth factors were found to enhance HCC cell proliferation, as well as tu-mor invasion and metastasis, via the activation of the Ras/Raf-1/extracellular signal-regulated kinase (ERK) pathway (Nonomura, Ohta et al, 1987;Pang, Yuen et al, 2004;Tsuboi, Ichida et al, 2004). Also, overexpression of Ras genes is common in human HCC tissue.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in RAS Guanyl-releasing Protein 3 are Associated with Chronic Liver Disease and Hepatocellular Carcinoma in a Korean Population

Oh¹,

Lee²,

Kim³

et al. 2008

Genomics & Informatics

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RAS guanyl-releasing protein 3 (RasGRP3), a member of the Ras subfamily of GTPases, functions as a guanosine triphosphate (GTP)/guanosine diphosphate (GDP)-regulated switch that cycles between inactive GDP-and active GTP-bound states during signal transduction. Various growth factors enhance hepatocellular carcinoma (HCC) proliferation via activation of the Ras/Raf-1/ extracellular signal-regulated kinase (ERK) pathway, which depends on RasGRP3 activation. We investigated the relationship between polymorphisms in RasGRP3 and progression of hepatitis B virus (HBV)-infected HCC in a Korean population. Nineteen RasGRP3 SNPs were genotyped in 206 patients with chronic liver disease (CLD) and 86 patients with HCC. Our results revealed that the T allele of the rs7597095 SNP and the C allele of the rs7592762 SNP increased susceptibility to HCC (OR=1.55, p=0.04 and OR=1.81∼2.61, p=0.01∼0.03, respectively). Moreover, patients who possessed the haplotype (ht) 1 (A-T-C-G) or diplotype (dt) 1 (ht1/ht1) variations had increased susceptibility to HCC (OR=1.79 ∼2.78, p=0.01∼0.03). In addition, we identified an association between haplotype1 (ht1) and the age of HCC onset; the age of HCC onset are earlier in ht1 +/+ than ht1 +/-or ht1 -/-(HR=0.42∼0.66, p=0.006∼0.015). Thus, our data suggest that RasGRP3 SNPs are significantly associated with an increased risk of developing HCC.

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Overexpression of extracellular signal‐regulated protein kinase and its correlation with proliferation in human hepatocellular carcinoma

Abstract: Our findings suggest that ERK overexpression contributes to the proliferation of HCC.

Cited by 69 publications

References 22 publications

Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

PDGF essentially links TGF-β signaling to nuclear β-catenin accumulation in hepatocellular carcinoma progression

Polymorphisms in RAS Guanyl-releasing Protein 3 are Associated with Chronic Liver Disease and Hepatocellular Carcinoma in a Korean Population

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