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RNA interference against hepatic epidermal growth factor receptor has suppressive effects on liver regeneration in
Shirish Paranjpe1, William C Bowen, George C Tseng
1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Abstract:
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 beta. The decrease in the ratio of C/EBP alpha to C/EBP beta 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.
Insights
Epidermal growth factor receptor (EGFR) plays a unique role in liver regeneration after partial hepatectomy (PHx). Inhibiting EGFR reduces hepatocyte proliferation but does not impede liver regrowth, indicating distinct pathway contributions.
Area of Science:
- Hepatology
- Molecular Biology
- Cell Signaling
Background:
- Liver regeneration is a complex process involving multiple growth factors and signaling pathways.
- Epidermal growth factor receptor (EGFR) signaling is activated early after partial hepatectomy (PHx).
Purpose of the Study:
- To investigate the specific role of EGFR in liver regeneration following PHx.
- To determine if EGFR signaling is compensated by other pathways like MET during liver regrowth.
Main Methods:
- Utilized EGFR-specific short hairpin RNAs (shEGFR) to inhibit EGFR expression in regenerating rat livers.
- Assessed EGFR mRNA and protein levels, cell proliferation markers (BrdU incorporation, mitoses), and key signaling molecules.
Main Results:
- EGFR inhibition decreased hepatocyte proliferation and altered downstream signaling pathways, including MET, Src, PI3K-Akt, and STAT3.
- Despite reduced proliferation, liver weight restoration occurred, with hepatocytes showing increased size.
- EGFR and MET pathways demonstrated unique, non-compensatory roles in liver regeneration.
Conclusions:
- EGFR signaling uniquely contributes to hepatocyte proliferation during liver regeneration.
- EGFR inhibition does not prevent liver regeneration, highlighting the distinct functions of EGFR and MET pathways.
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