Mechanisms of hepatocyte growth factor–mediated and epidermal growth factor–mediated signaling in transdifferentiation of rat hepatocytes to biliary epithelium

Limaye, Pallavi B.; Bowen, William C.; Orr, Anne; Luo, Jianhua; Tseng, George C.; Michalopoulos, George K.

doi:10.1002/hep.22221

Cited by 102 publications

(95 citation statements)

References 43 publications

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“…Previous studies also showed that HGF was another promoter of the phenotypic changes of mature hepatocytes. 18,21,22 However, as shown in Figure 1a, our preliminary studies failed to demonstrate significant changes in CK19 and AFP expression after HGF treatment in PLC-5.…”

Section: Discussionmentioning

confidence: 66%

“…[18][19][20][21][22] In these studies, EGF has been shown to be an essential promoter of the phenotypic transdifferentiation of mature hepatocytes. 18,[20][21][22] This study demonstrated that EGF could induce phenotypic changes in HCC similar to those seen in non-cancerous mature hepatocytes. Previous studies also showed that HGF was another promoter of the phenotypic changes of mature hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

“…17 Previous studies showed that rat hepatocytes had a potential to differentiate into bile duct-like cells in vitro. [18][19][20][21][22] In these studies, epidermal growth factor (EGF) and hepatocytes growth factor (HGF) are potent inducers of biliary phenotype in rat hepatocytes. [18][19][20][21][22] Transforming growth factor-b1 (TGF-b1) and basic fibroblast growth factor (FGF-b) are also well-known growth factors that have key roles in the development and differentiation of the liver.…”

mentioning

confidence: 99%

“…[18][19][20][21][22] In these studies, epidermal growth factor (EGF) and hepatocytes growth factor (HGF) are potent inducers of biliary phenotype in rat hepatocytes. [18][19][20][21][22] Transforming growth factor-b1 (TGF-b1) and basic fibroblast growth factor (FGF-b) are also well-known growth factors that have key roles in the development and differentiation of the liver. [23][24][25][26] These observations suggest that the expression of CK19, one of the characters of biliary CK, may be induced in HCC after stimuli by a certain kind of growth factors, accounting for the development of CK19-positive HCC.…”

mentioning

confidence: 99%

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Epidermal growth factor induces cytokeratin 19 expression accompanied by increased growth abilities in human hepatocellular carcinoma

Yoneda

Sato

Kitao

et al. 2011

Laboratory Investigation

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Cytokeratin (CK) 19-positive hepatocellular carcinoma (HCC) has been reported to have a poor prognosis. The mechanism of the development of CK19-positive HCC remains to be studied. To clarify this, in vitro experiments were performed using human HCC cell lines HepG2), and the phenotypic changes after stimulation with several growth factors were examined using quantitative reverse transcriptase PCR, western blotting, and immunofluorescence staining. In vivo experiments using human HCC specimens obtained from a total of 78 patients and clinicopathological analysis were also performed. Among the growth factors tested, epidermal growth factor (EGF) had prominent effects on inducing CK19 expression in PLC-5 and HepG2, which was accompanied by the reduced expression of a-fetoprotein in PLC-5. The induction of CK19 expression after EGF stimulation was accompanied by the phosphorylation of c-Jun-N-terminal kinase (JNK)/stress-activated protein kinase, which was blocked by the addition of JNK inhibitors. EGF also increased proliferative abilities and invasive properties of the HCC cell lines. In vivo, 9 (12%) of 78 HCC cases showed positive immunohistochemical staining of CK19. The extent of positive immunhistochemical signals of EGF, EGF receptor (EGFR), and JNK expression was significantly intense in CK-19-positive HCC than those of CK19-negative HCC. Clinicopathological analysis showed that CK19-positive HCC had a high incidence of portal vein invasion, extrahepatic metastasis and an early relapse, which was associated with the worsened 2-year disease free survival. These results indicate that the activation of the EGF-EGFR signaling pathway is associated with the development of CK19-positive HCC, and the EGF-induced increase in growth abilities of HCC may account for the poor prognosis of the patients.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Epidermal growth factor induces cytokeratin 19 expression accompanied by increased growth abilities in human hepatocellular carcinoma

Yoneda

Sato

Kitao

et al. 2011

Laboratory Investigation

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“…[9][10][11] Recently, we found that tumor necrosis factor-α (TNF-α) significantly enhanced ductular transdifferentiation (Nishikawa et al, submitted for publication).…”

Section: Introductionmentioning

confidence: 99%

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Sone

Nishikawa

Nagahama

et al. 2012

The American Journal of Pathology

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We previously demonstrated that mature rat hepatocytes transdifferentiate to bile ductular cells when cultured in a three-dimensional collagen-rich matrix. Here, we show that the phenotype of transdifferentiated hepatocytes can be reversed by modulating culture conditions. Spheroidal aggregates of hepatocytes were cultured within a collagen gel matrix in the presence of serum and tumor necrosis factor-α. Spheroids transformed into ductular structures composed of small cuboidal cells, lost the expression of hepatocytic markers, while aberrantly expressed bile ductular markers. The transdifferentiated cells were then retrieved from the gels, plated on Matrigel-coated surfaces, and cultured in serum-free media. Cells spontaneously formed spheroidal aggregates and recovered hepatocytic phenotype. While Dexamethasone (Dex), which suppressed the phosphorylation of ERK and Jun N-terminal kinase, facilitated the recovery, the combination with interleukin-6 or oncostatin M resulted in the recovery of HNF-4α protein expression and the typical hepatocytic morphology and a decrease in the expression of bile ductular markers. A cDNA microarray analysis revealed that the hepatocyte-specific mRNA expression profile was recovered in these cells. Our results demonstrate that hepatocytes are able to recover their phenotypes following bile ductular transdifferentiation, suggesting that hepatocytic and bile ductular phenotypes may be mutually reversible.4

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Liver Cancer Stem Cells and Hepatocarcinogenesis

Okabe

Hayashi

Ishimoto

et al. 2015

Principles of Stem Cell Biology and Cancer

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Mechanisms of hepatocyte growth factor–mediated and epidermal growth factor–mediated signaling in transdifferentiation of rat hepatocytes to biliary epithelium

Abstract: Taken together, these data indicate that hepatocyte to BE transdifferentiation is regulated by HGF and EGF receptors and that PI3 kinase-mediated signaling independent of AKT is a crucial component of the transdifferentiation process.

Cited by 102 publications

References 43 publications

Epidermal growth factor induces cytokeratin 19 expression accompanied by increased growth abilities in human hepatocellular carcinoma

Epidermal growth factor induces cytokeratin 19 expression accompanied by increased growth abilities in human hepatocellular carcinoma

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Liver Cancer Stem Cells and Hepatocarcinogenesis

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