Cell cycle effects resulting from inhibition of hepatocyte growth factor and its receptor c-Met in regenerating rat livers by RNA interference

Paranjpe, Shirish; Bowen, William C.; Bell, Aaron; Nejak‐Bowen, Kari; Luo, Jianhua; Michalopoulos, George K.

doi:10.1002/hep.21570

Cited by 88 publications

(68 citation statements)

References 38 publications

(46 reference statements)

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“…31 As seen in Figure, 2B, there was significant suppression in BrdU incorporation in shEGFR-treated rats compared with controls. Even though the percentage qRT-PCR analysis of EGFR mRNA in shEGFR-treated rats and controls at time points indicated after PHx.…”

Section: Brdu Labeling Indexmentioning

confidence: 66%

“…[27][28][29] To avoid pitfalls resulting from adaptations to gene loss 30 and histopathological alterations, we investigated the role of EGFR in liver regeneration in rats after a two-thirds PHx by using short hairpin silencing RNA (shRNA) targeting EGFR, a method we have recently applied for the HGF receptor (c-Met). 31 Our data show severe effects on hepatocyte proliferation and compensatory increases in expression of ErbB-3, ErbB-2, MET, and Src. Liver weight was restored in part by increase in hepatocyte size.…”

mentioning

confidence: 59%

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RNA Interference Against Hepatic Epidermal Growth Factor Receptor Has Suppressive Effects on Liver Regeneration in Rats

Paranjpe

Bowen

Tseng

et al. 2010

The American Journal of Pathology

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Liver regeneration after a two-thirds partial hepatectomy (PHx) is a complex process requiring interaction and cooperation of many growth factors and cytokines and cross talk between multiple pathways. Along with hepatocyte growth factor and its receptor MET (HGF-MET), the epidermal growth factor receptor (EGFR) signaling pathway is activated within 60 minutes after PHx. To investigate the role of EGFR in liver regeneration, we used two EGFR-specific short hairpin silencing RNAs to inhibit EGFR expression in regenerating normal rat liver. Suppression of EGFR mRNA and protein was evident in treated rats. There was also a demonstrable decrease but not complete elimination of bromo-deoxyuridine incorporation and mitoses at 24 hours after PHx. In addition, we observed up-regulation of MET and Src as well as activation of the ErbB-3-ErbB-2-PI3K-Akt pathway and down-regulation of STAT 3, cyclin D1, cyclin E1, p21, and C/EBP ␤. The decrease in the ratio of C/EBP ␣ to C/EBP ␤ known to occur after PHx was offset in shEGFR-treated rats. Despite suppression of hepatocyte proliferation lasting into day 3 after PHx, liver weight restoration occurred. Interestingly, hepatocytes in shEGFR-treated rats were considerably larger when compared with ScrRNA-treated controls. The data indicate that although the MET and EGFR pathways are similar, the contributions made by MET and EGFR are unique and are not compensated by each other or other cytokines. Partial hepatectomy (PHx), in which two thirds of the rat liver is surgically removed, has been extensively used to study the highly complex phenomenon of liver regeneration. Although hepatocytes in normal adult liver are quiescent and rarely divide, they do retain an astounding ability to reenter the cell cycle and regenerate on surgical insult or injury. PHx in rats/mice results in rapid induction of more than 100 genes that are not expressed in the normal resting liver.1 A rapid up-regulation of genes encoding transcriptional factors like AP1 breakdown of extracellular matrix by uPA and release of pre-existing stores of HGF is observed within 60 minutes of a PHx. 2The hepatocytes leave the quiescent G0 phase and enter the cell cycle. Methods to identify extrahepatic signals leading to liver regeneration have included mitogenic effects on hepatocyte cultures, stimulation of DNA synthesis in the liver of normal (unoperated) animals, and decrease in regeneration-related events in animals genetically or pharmacologically depleted of the agent under study. Of the various agents implicated in liver regeneration, HGF and ligands of the epidermal growth factor receptor (EGFR) are the only ones that stimulate DNA synthesis in hepatocyte cultures maintained in chemically defined media.3 They are also the only ones that stimulate DNA synthesis in the liver of normal mice and rats. 4 -6 HGF and EGF signaling pathways are activated within 60 minutes after a PHx, 7,8 as evidenced by tyrosine phosphorylation of MET and EGFR within 30 to 60 minutes after PHx. There is evidence of cross talk and c...

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Section: Brdu Labeling Indexmentioning

confidence: 66%

mentioning

confidence: 59%

RNA Interference Against Hepatic Epidermal Growth Factor Receptor Has Suppressive Effects on Liver Regeneration in Rats

Paranjpe

Bowen

Tseng

et al. 2010

The American Journal of Pathology

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“…Plasmid-based expression of short hairpin RNA has been used to study the role(s) of HGF/c-Met and EGFR during liver regeneration in rats 15,16 , and stable delivery of pools of short hairpin RNAs into mouse livers lead to the identification of the kinase MKK4 as a major regulator of liver regeneration 17 . Additional siRNA delivery systems were invented to improve tissue specificity and low-dose efficacy.…”

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confidence: 99%

Knockdown and knockout of β1-integrin in hepatocytes impairs liver regeneration through inhibition of growth factor signalling

et al. 2014

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The liver has a unique regenerative capability, which involves extensive remodelling of cell-cell and cell-matrix contacts. Here we study the role of integrins in mouse liver regeneration using Cre/loxP-mediated gene deletion or intravenous delivery of b1-integrin siRNA formulated into nanoparticles that predominantly target hepatocytes. We show that although short-term loss of b1-integrin has no obvious consequences for normal livers, partial hepatectomy leads to severe liver necrosis and reduced hepatocyte proliferation. Mechanistically, loss of b1-integrin in hepatocytes impairs ligand-induced phosphorylation of the epidermal growth factor and hepatocyte growth factor receptors, thereby attenuating downstream receptor signalling in vitro and in vivo. These results identify a crucial role and novel mechanism of action of b1-integrins in liver regeneration and demonstrate that protein depletion by nanoparticle-based delivery of specific siRNA is a powerful strategy to study gene function in the regenerating liver.

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“…Mutations of BMPRII have been found in pancreatic tumors [135] and missense germline mutations of ALK3 are found in 20% of Juvenile Polyposis Syndrome patients [136]. Epigenetic mechanisms, such as hypermethylation of the BMP2 promoter in gastric carcinomas, has also been reported [137]. BMPs have been associated with control of proliferation in tumor cells (both positively and negatively, extensively reviewed in [128], with promotion of migration and invasion [37,132,138,139], EMT phenomena [139], metastasic processes [140][141][142] and also with pro-angiogenic effects [143].…”

Section: Bmps In Liver Carcinogenesismentioning

confidence: 99%

BMPS and Liver: More Questions than Answers

Herrera¹,

Sánchez²,

Fabregat³

2012

Current Pharmaceutical Design

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Cell cycle effects resulting from inhibition of hepatocyte growth factor and its receptor c-Met in regenerating rat livers by RNA interference

Cited by 88 publications

References 38 publications

RNA Interference Against Hepatic Epidermal Growth Factor Receptor Has Suppressive Effects on Liver Regeneration in Rats

RNA Interference Against Hepatic Epidermal Growth Factor Receptor Has Suppressive Effects on Liver Regeneration in Rats

Knockdown and knockout of β1-integrin in hepatocytes impairs liver regeneration through inhibition of growth factor signalling

BMPS and Liver: More Questions than Answers

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