Loss of hepatocyte ERBB3 but not EGFR impairs hepatocarcinogenesis.
Epidermal growth factor receptor (EGFR) and ERBB3 have been implicated in hepatocellular carcinogenesis (HCC). However, it is not known whether altering the activity of either EGFR or ERBB3 affects HCC development. We now show that Egfr(Dsk5) mutant mice, which have a gain-of-function allele that increases basal EGFR kinase activity, develop spontaneous HCC by 10 mo of age. Their tumors show increased activation of EGFR, ERBB2, and ERBB3 as well as AKT and ERK1,2. Hepatocyte-specific models of EGFR and ERBB3 gene ablation were generated to evaluate how the loss of these genes affected tumor progression. Loss of either receptor tyrosine kinase did not alter liver development or regenerative liver growth following carbon tetrachloride injection. However, using a well-characterized model of HCC in which N-nitrosodiethylamine is injected into 14-day-old mice, we discovered that loss of hepatocellular ERBB3 but not EGFR, which occurred after tumor initiation, retarded liver tumor formation and cell proliferation. We found no evidence that this was due to increased apoptosis or diminished phosphatidylinositol-3-kinase activity in the ERBB3-null cells. However, the relative amount of phospho-STAT3 was diminished in tumors derived from these mice, suggesting that ERBB3 may promote HCC through STAT3 activation.
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee; lawrence.a.scheving@vanderbilt.edu.
Lawrence A
LA
Scheving
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee;
Xiuqi
X
Zhang
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee;
Mary C
MC
Stevenson
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee;
Michael A
MA
Weintraub
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee;
Annam
A
Abbasi
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee;
Andrea M
AM
Clarke
Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas; and Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas.
David W
DW
Threadgill
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee;
William E
WE
Russell
D000367:Age Factors; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004052:Diethylnitrosamine; D066246:ErbB Receptors / Q000172:deficiency* / Q000235:genetics; D005838:Genotype; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008115:Liver Regeneration; D008297:Male; D057507:Mice, 129 Strain; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D010641:Phenotype; D010766:Phosphorylation; D020893:Receptor, ErbB-3 / Q000172:deficiency* / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D004052:Diethylnitrosamine; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D020893:Receptor, ErbB-3
DEN; Dsk5; EGFR; ERBB3; hepatocarcinogenesis