Premium
Liver Regeneration Deficit in Mice Following EGFR and Met Elimination
Author(s) -
PARANJPE SHIRISH,
Bowen William,
Haynes Meagan,
Mars Wendy,
Orr Anne,
Paranjpe Tejas,
Luo Jianhua,
Michalopoulos Amantha,
Michalopoulos George
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.416.8
Subject(s) - liver regeneration , tyrosine aminotransferase , western blot , regeneration (biology) , hepatectomy , kinase , receptor tyrosine kinase , endocrinology , biology , medicine , chemistry , pharmacology , microbiology and biotechnology , biochemistry , gene , enzyme , enzyme inducer , surgery , resection
Acute loss of liver mass following toxic or surgical means elicits hepatic regeneration and restoration of liver tissue to its original mass, indicating a tightly regulated growth process. A two‐thirds partial hepatectomy (PHx) in mice and rats results in rapid induction of more than 100 genes, (that are not expressed in resting liver) & activation of multiple signaling pathways. EGFR & MET, the two major mitogenic receptor tyrosine kinases, are activated within 15 ‐ 30 minutes following a PHx. The MET‐EGFR signaling pathway plays a significant role in is activated within 15‐30 minute following a PHx in mice and rats. The role played by these two pathways during liver regeneration was investigated by utilizing mice that had c‐met deleted in the liver using a tamoxiphen inducible Cre‐loxP system. Following deletion of c‐met, mice were administered (80mg/kg, i.p) of Canertinib, a pan EGFR inhibitor. Mice were injected a day before PHx and then everyday for seven days. A partial hepatectomy was carried out two hours later. Appropriate vehicle controls were also used. In mice treated with Tyrosine kinase inhibitors, pEGFR levels were significantly reduced compared to vehicle treated controls. A significant reduction in Ki67 labeling was also evident, as was a reduction in liver to body wight ratio, suggesting a liver regeneration deficit. Microarray analyses of inhibitor and vehicle treated controls indicated significant down regulation of cell cycle related genes, that was confirmed by western blot analyses. There appears to be no redundancy and compensatory scheme for liver regeneration when both Met and EGFR are blocked.