Targeting MEK is effective chemoprevention of hepatocellular carcinoma in TGF-α-transgenic mice

Sabrina C. Wentz, Huangbing Wu, Michele Yip-Schneider, Matthew Hennig, Patrick J. Klein, Judith Sebolt-Leopold, C. Schmidt

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Hepatocellular carcinoma (HCC) causes 600,000 mortalities per year worldwide. Previous studies from our lab provide evidence for altered mitogen-activated protein kinase and extracellular signal-regulated kinase kinase (MEK) signaling in HCC pathogenesis. We hypothesized that pharmacologic targeting of MEK may prevent HCC. Transforming growth factor-alpha-transgenic mice (CD1-MT42) exposed to diethylnitrosamine were randomized to 20 (trial I) or 35 (trial II) weeks of MEK inhibitor PD0325901 (1, 10 mg/kg) or control via orogastric gavage. Ten HCC (44%) formed in trial I controls versus 0 in treatment arms (p∈<∈0.05). Fourteen HCC (50%) formed in trial II controls versus 1 (9%) in treatment arms (p∈<∈0.05). Mean HCC volume was 578 mm3 in control versus 46 mm3 in the single tumor formed in trial II. In trial I, foci of altered hepatocytes (FAH) formed in 78% of control versus 40% and 0% (1 and 10 mg/kg PD0325901) in treatment arms (p∈<∈0.05). In trial II, incidence of FAH was 80% in control versus 20% and 50% (1 and 10 mg/kg PD0325901) in treatment arms (p∈<∈0.05). Hepatocyte expression of phosphorylated extracellular signal-regulated kinase dose-dependently decreased in trial I but remained the same in trial II. Control and treated HCC demonstrated similar proliferation rates, but apoptosis appeared increased with treatment. MEK targeting is effective HCC chemoprevention, perhaps by lowering the apoptotic threshold.

Original languageEnglish
Pages (from-to)30-37
Number of pages8
JournalJournal of Gastrointestinal Surgery
Volume12
Issue number1
DOIs
StatePublished - Jan 2008

Fingerprint

Mitogen-Activated Protein Kinase Kinases
Chemoprevention
Transgenic Mice
Hepatocellular Carcinoma
Hepatocytes
Extracellular Signal-Regulated MAP Kinases
MAP Kinase Kinase Kinases
Therapeutics
Diethylnitrosamine
Transforming Growth Factor alpha
Mitogen-Activated Protein Kinases
Apoptosis
Mortality
Incidence

Keywords

  • Chemoprevention
  • Hepatocellular carcinoma
  • Liver cancer
  • MEK/ERK
  • PD0325901

ASJC Scopus subject areas

  • Surgery

Cite this

Targeting MEK is effective chemoprevention of hepatocellular carcinoma in TGF-α-transgenic mice. / Wentz, Sabrina C.; Wu, Huangbing; Yip-Schneider, Michele; Hennig, Matthew; Klein, Patrick J.; Sebolt-Leopold, Judith; Schmidt, C.

In: Journal of Gastrointestinal Surgery, Vol. 12, No. 1, 01.2008, p. 30-37.

Research output: Contribution to journalArticle

Wentz, Sabrina C. ; Wu, Huangbing ; Yip-Schneider, Michele ; Hennig, Matthew ; Klein, Patrick J. ; Sebolt-Leopold, Judith ; Schmidt, C. / Targeting MEK is effective chemoprevention of hepatocellular carcinoma in TGF-α-transgenic mice. In: Journal of Gastrointestinal Surgery. 2008 ; Vol. 12, No. 1. pp. 30-37.
@article{b5b4881dea934ef78652e59456c209da,
title = "Targeting MEK is effective chemoprevention of hepatocellular carcinoma in TGF-α-transgenic mice",
abstract = "Hepatocellular carcinoma (HCC) causes 600,000 mortalities per year worldwide. Previous studies from our lab provide evidence for altered mitogen-activated protein kinase and extracellular signal-regulated kinase kinase (MEK) signaling in HCC pathogenesis. We hypothesized that pharmacologic targeting of MEK may prevent HCC. Transforming growth factor-alpha-transgenic mice (CD1-MT42) exposed to diethylnitrosamine were randomized to 20 (trial I) or 35 (trial II) weeks of MEK inhibitor PD0325901 (1, 10 mg/kg) or control via orogastric gavage. Ten HCC (44{\%}) formed in trial I controls versus 0 in treatment arms (p∈<∈0.05). Fourteen HCC (50{\%}) formed in trial II controls versus 1 (9{\%}) in treatment arms (p∈<∈0.05). Mean HCC volume was 578 mm3 in control versus 46 mm3 in the single tumor formed in trial II. In trial I, foci of altered hepatocytes (FAH) formed in 78{\%} of control versus 40{\%} and 0{\%} (1 and 10 mg/kg PD0325901) in treatment arms (p∈<∈0.05). In trial II, incidence of FAH was 80{\%} in control versus 20{\%} and 50{\%} (1 and 10 mg/kg PD0325901) in treatment arms (p∈<∈0.05). Hepatocyte expression of phosphorylated extracellular signal-regulated kinase dose-dependently decreased in trial I but remained the same in trial II. Control and treated HCC demonstrated similar proliferation rates, but apoptosis appeared increased with treatment. MEK targeting is effective HCC chemoprevention, perhaps by lowering the apoptotic threshold.",
keywords = "Chemoprevention, Hepatocellular carcinoma, Liver cancer, MEK/ERK, PD0325901",
author = "Wentz, {Sabrina C.} and Huangbing Wu and Michele Yip-Schneider and Matthew Hennig and Klein, {Patrick J.} and Judith Sebolt-Leopold and C. Schmidt",
year = "2008",
month = "1",
doi = "10.1007/s11605-007-0396-4",
language = "English",
volume = "12",
pages = "30--37",
journal = "Journal of Gastrointestinal Surgery",
issn = "1091-255X",
publisher = "Springer New York",
number = "1",

}

TY - JOUR

T1 - Targeting MEK is effective chemoprevention of hepatocellular carcinoma in TGF-α-transgenic mice

AU - Wentz, Sabrina C.

AU - Wu, Huangbing

AU - Yip-Schneider, Michele

AU - Hennig, Matthew

AU - Klein, Patrick J.

AU - Sebolt-Leopold, Judith

AU - Schmidt, C.

PY - 2008/1

Y1 - 2008/1

N2 - Hepatocellular carcinoma (HCC) causes 600,000 mortalities per year worldwide. Previous studies from our lab provide evidence for altered mitogen-activated protein kinase and extracellular signal-regulated kinase kinase (MEK) signaling in HCC pathogenesis. We hypothesized that pharmacologic targeting of MEK may prevent HCC. Transforming growth factor-alpha-transgenic mice (CD1-MT42) exposed to diethylnitrosamine were randomized to 20 (trial I) or 35 (trial II) weeks of MEK inhibitor PD0325901 (1, 10 mg/kg) or control via orogastric gavage. Ten HCC (44%) formed in trial I controls versus 0 in treatment arms (p∈<∈0.05). Fourteen HCC (50%) formed in trial II controls versus 1 (9%) in treatment arms (p∈<∈0.05). Mean HCC volume was 578 mm3 in control versus 46 mm3 in the single tumor formed in trial II. In trial I, foci of altered hepatocytes (FAH) formed in 78% of control versus 40% and 0% (1 and 10 mg/kg PD0325901) in treatment arms (p∈<∈0.05). In trial II, incidence of FAH was 80% in control versus 20% and 50% (1 and 10 mg/kg PD0325901) in treatment arms (p∈<∈0.05). Hepatocyte expression of phosphorylated extracellular signal-regulated kinase dose-dependently decreased in trial I but remained the same in trial II. Control and treated HCC demonstrated similar proliferation rates, but apoptosis appeared increased with treatment. MEK targeting is effective HCC chemoprevention, perhaps by lowering the apoptotic threshold.

AB - Hepatocellular carcinoma (HCC) causes 600,000 mortalities per year worldwide. Previous studies from our lab provide evidence for altered mitogen-activated protein kinase and extracellular signal-regulated kinase kinase (MEK) signaling in HCC pathogenesis. We hypothesized that pharmacologic targeting of MEK may prevent HCC. Transforming growth factor-alpha-transgenic mice (CD1-MT42) exposed to diethylnitrosamine were randomized to 20 (trial I) or 35 (trial II) weeks of MEK inhibitor PD0325901 (1, 10 mg/kg) or control via orogastric gavage. Ten HCC (44%) formed in trial I controls versus 0 in treatment arms (p∈<∈0.05). Fourteen HCC (50%) formed in trial II controls versus 1 (9%) in treatment arms (p∈<∈0.05). Mean HCC volume was 578 mm3 in control versus 46 mm3 in the single tumor formed in trial II. In trial I, foci of altered hepatocytes (FAH) formed in 78% of control versus 40% and 0% (1 and 10 mg/kg PD0325901) in treatment arms (p∈<∈0.05). In trial II, incidence of FAH was 80% in control versus 20% and 50% (1 and 10 mg/kg PD0325901) in treatment arms (p∈<∈0.05). Hepatocyte expression of phosphorylated extracellular signal-regulated kinase dose-dependently decreased in trial I but remained the same in trial II. Control and treated HCC demonstrated similar proliferation rates, but apoptosis appeared increased with treatment. MEK targeting is effective HCC chemoprevention, perhaps by lowering the apoptotic threshold.

KW - Chemoprevention

KW - Hepatocellular carcinoma

KW - Liver cancer

KW - MEK/ERK

KW - PD0325901

UR - http://www.scopus.com/inward/record.url?scp=38349071703&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38349071703&partnerID=8YFLogxK

U2 - 10.1007/s11605-007-0396-4

DO - 10.1007/s11605-007-0396-4

M3 - Article

C2 - 17987349

AN - SCOPUS:38349071703

VL - 12

SP - 30

EP - 37

JO - Journal of Gastrointestinal Surgery

JF - Journal of Gastrointestinal Surgery

SN - 1091-255X

IS - 1

ER -