Evidence that reduction of hepatocyte growth factor (HGF) is not required for peroxisome proliferator-induced hepatocyte proliferation

Andras Kiss, Roberto Ortiz-Aguayo, Richard Sharp, Glenn Merlino, Snorri S. Thorgeirsson, Frank J. Gonzalez, Jeffrey Maurice Peters

Research output: Contribution to journalComment/debate

1 Citation (Scopus)

Abstract

The mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis are not understood. Because of the uncertainty of human cancer risk associated with peroxisome proliferators, delineating the mechanisms of carcinogenesis by these agents is of great interest. Alterations in liver growth factors were postulated to contribute to the carcinogenic effect of peroxisome proliferators. Administration of these compounds to rodents results in down-regulation of hepatocyte growth factor (HGF) and supplementing culture medium with HGF is reported to suppress cell proliferation of preneoplastic and neoplastic cells from WY-14,643-treated livers. Combined, these observations suggest that reduced levels of hepatic HGF contribute to the mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis. To determine if HGF can prevent the effects of peroxisome proliferators in liver, the short-term influence of WY-14,643 in two different lines of HGF transgenic mice was examined. Mice were fed either a control diet or one containing 0.1% WY-14-643 for one week. Hepatomegaly was found in both HGF transgenic mouse lines fed WY-14,643 compared with controls. Additionally, hepatic expression of typical mRNA markers of peroxisome proliferation including those encoding peroxisomal fatty acid metabolizing enzymes and cell cycle control proteins were all significantly elevated in HGF transgenic mice fed WY-14,643 compared with controls. Down-regulation of HGF was found to be dependent on PPARα since lower levels of HGF mRNA and protein were observed in wild-type mice fed WY-14,643 for 1 week and not in similarly treated PPARα-null mice. These results demonstrate that the early increase in hepatic mRNAs associated with peroxisome and cell proliferation induced by WY-14,643 treatment can not be prevented by overexpression of HGF in vivo.

Original languageEnglish (US)
Pages (from-to)975-979
Number of pages5
JournalCarcinogenesis
Volume22
Issue number6
StatePublished - Jun 19 2001

Fingerprint

Peroxisome Proliferators
Hepatocyte Growth Factor
Hepatocytes
Liver
Transgenic Mice
Peroxisome Proliferator-Activated Receptors
Peroxisomes
Messenger RNA
Down-Regulation
Cell Proliferation
Cell Cycle Proteins
Hepatomegaly
Cell Cycle Checkpoints
pirinixic acid
Uncertainty
Culture Media
Rodentia
Carcinogenesis
Fatty Acids

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Kiss, A., Ortiz-Aguayo, R., Sharp, R., Merlino, G., Thorgeirsson, S. S., Gonzalez, F. J., & Peters, J. M. (2001). Evidence that reduction of hepatocyte growth factor (HGF) is not required for peroxisome proliferator-induced hepatocyte proliferation. Carcinogenesis, 22(6), 975-979.
Kiss, Andras ; Ortiz-Aguayo, Roberto ; Sharp, Richard ; Merlino, Glenn ; Thorgeirsson, Snorri S. ; Gonzalez, Frank J. ; Peters, Jeffrey Maurice. / Evidence that reduction of hepatocyte growth factor (HGF) is not required for peroxisome proliferator-induced hepatocyte proliferation. In: Carcinogenesis. 2001 ; Vol. 22, No. 6. pp. 975-979.
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title = "Evidence that reduction of hepatocyte growth factor (HGF) is not required for peroxisome proliferator-induced hepatocyte proliferation",
abstract = "The mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis are not understood. Because of the uncertainty of human cancer risk associated with peroxisome proliferators, delineating the mechanisms of carcinogenesis by these agents is of great interest. Alterations in liver growth factors were postulated to contribute to the carcinogenic effect of peroxisome proliferators. Administration of these compounds to rodents results in down-regulation of hepatocyte growth factor (HGF) and supplementing culture medium with HGF is reported to suppress cell proliferation of preneoplastic and neoplastic cells from WY-14,643-treated livers. Combined, these observations suggest that reduced levels of hepatic HGF contribute to the mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis. To determine if HGF can prevent the effects of peroxisome proliferators in liver, the short-term influence of WY-14,643 in two different lines of HGF transgenic mice was examined. Mice were fed either a control diet or one containing 0.1{\%} WY-14-643 for one week. Hepatomegaly was found in both HGF transgenic mouse lines fed WY-14,643 compared with controls. Additionally, hepatic expression of typical mRNA markers of peroxisome proliferation including those encoding peroxisomal fatty acid metabolizing enzymes and cell cycle control proteins were all significantly elevated in HGF transgenic mice fed WY-14,643 compared with controls. Down-regulation of HGF was found to be dependent on PPARα since lower levels of HGF mRNA and protein were observed in wild-type mice fed WY-14,643 for 1 week and not in similarly treated PPARα-null mice. These results demonstrate that the early increase in hepatic mRNAs associated with peroxisome and cell proliferation induced by WY-14,643 treatment can not be prevented by overexpression of HGF in vivo.",
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Kiss, A, Ortiz-Aguayo, R, Sharp, R, Merlino, G, Thorgeirsson, SS, Gonzalez, FJ & Peters, JM 2001, 'Evidence that reduction of hepatocyte growth factor (HGF) is not required for peroxisome proliferator-induced hepatocyte proliferation', Carcinogenesis, vol. 22, no. 6, pp. 975-979.

Evidence that reduction of hepatocyte growth factor (HGF) is not required for peroxisome proliferator-induced hepatocyte proliferation. / Kiss, Andras; Ortiz-Aguayo, Roberto; Sharp, Richard; Merlino, Glenn; Thorgeirsson, Snorri S.; Gonzalez, Frank J.; Peters, Jeffrey Maurice.

In: Carcinogenesis, Vol. 22, No. 6, 19.06.2001, p. 975-979.

Research output: Contribution to journalComment/debate

TY - JOUR

T1 - Evidence that reduction of hepatocyte growth factor (HGF) is not required for peroxisome proliferator-induced hepatocyte proliferation

AU - Kiss, Andras

AU - Ortiz-Aguayo, Roberto

AU - Sharp, Richard

AU - Merlino, Glenn

AU - Thorgeirsson, Snorri S.

AU - Gonzalez, Frank J.

AU - Peters, Jeffrey Maurice

PY - 2001/6/19

Y1 - 2001/6/19

N2 - The mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis are not understood. Because of the uncertainty of human cancer risk associated with peroxisome proliferators, delineating the mechanisms of carcinogenesis by these agents is of great interest. Alterations in liver growth factors were postulated to contribute to the carcinogenic effect of peroxisome proliferators. Administration of these compounds to rodents results in down-regulation of hepatocyte growth factor (HGF) and supplementing culture medium with HGF is reported to suppress cell proliferation of preneoplastic and neoplastic cells from WY-14,643-treated livers. Combined, these observations suggest that reduced levels of hepatic HGF contribute to the mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis. To determine if HGF can prevent the effects of peroxisome proliferators in liver, the short-term influence of WY-14,643 in two different lines of HGF transgenic mice was examined. Mice were fed either a control diet or one containing 0.1% WY-14-643 for one week. Hepatomegaly was found in both HGF transgenic mouse lines fed WY-14,643 compared with controls. Additionally, hepatic expression of typical mRNA markers of peroxisome proliferation including those encoding peroxisomal fatty acid metabolizing enzymes and cell cycle control proteins were all significantly elevated in HGF transgenic mice fed WY-14,643 compared with controls. Down-regulation of HGF was found to be dependent on PPARα since lower levels of HGF mRNA and protein were observed in wild-type mice fed WY-14,643 for 1 week and not in similarly treated PPARα-null mice. These results demonstrate that the early increase in hepatic mRNAs associated with peroxisome and cell proliferation induced by WY-14,643 treatment can not be prevented by overexpression of HGF in vivo.

AB - The mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis are not understood. Because of the uncertainty of human cancer risk associated with peroxisome proliferators, delineating the mechanisms of carcinogenesis by these agents is of great interest. Alterations in liver growth factors were postulated to contribute to the carcinogenic effect of peroxisome proliferators. Administration of these compounds to rodents results in down-regulation of hepatocyte growth factor (HGF) and supplementing culture medium with HGF is reported to suppress cell proliferation of preneoplastic and neoplastic cells from WY-14,643-treated livers. Combined, these observations suggest that reduced levels of hepatic HGF contribute to the mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis. To determine if HGF can prevent the effects of peroxisome proliferators in liver, the short-term influence of WY-14,643 in two different lines of HGF transgenic mice was examined. Mice were fed either a control diet or one containing 0.1% WY-14-643 for one week. Hepatomegaly was found in both HGF transgenic mouse lines fed WY-14,643 compared with controls. Additionally, hepatic expression of typical mRNA markers of peroxisome proliferation including those encoding peroxisomal fatty acid metabolizing enzymes and cell cycle control proteins were all significantly elevated in HGF transgenic mice fed WY-14,643 compared with controls. Down-regulation of HGF was found to be dependent on PPARα since lower levels of HGF mRNA and protein were observed in wild-type mice fed WY-14,643 for 1 week and not in similarly treated PPARα-null mice. These results demonstrate that the early increase in hepatic mRNAs associated with peroxisome and cell proliferation induced by WY-14,643 treatment can not be prevented by overexpression of HGF in vivo.

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M3 - Comment/debate

C2 - 11375907

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SP - 975

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JO - Carcinogenesis

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Kiss A, Ortiz-Aguayo R, Sharp R, Merlino G, Thorgeirsson SS, Gonzalez FJ et al. Evidence that reduction of hepatocyte growth factor (HGF) is not required for peroxisome proliferator-induced hepatocyte proliferation. Carcinogenesis. 2001 Jun 19;22(6):975-979.