CD133+ liver cancer stem cells from methionine adenosyl transferase 1A-deficient mice demonstrate resistance to transforming growth factor (TGF)-β-induced apoptosis

Wei Ding, Marialena Mouzaki, Hanning You, Joshua C. Laird, Jose Mato, Shelly C. Lu, C. Bart Rountree

Research output: Contribution to journalArticle

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Abstract

Methionine adenosyltransferase (MAT) is an essential enzyme required for S-adenosylmethionine biosynthesis. Hepatic MAT activity falls during chronic liver injury, and mice lacking Mat1a develop spontaneous hepatocellular carcinoma by 18 months. We have previously demonstrated that CD133+CD45- oval cells isolated from 16-month-old Mat1a-/- mice represent a liver cancer stem cell population. The transforming growth factor β (TGF-β) pathway constitutes a central signaling network in proliferation, apoptosis, and tumorigenesis. In this study, we tested the response of tumorigenic liver stem cells to TGF-β. CD133+CD45- oval cells were isolated from premalignant 16-month-old Mat1a-/- mice by flow cytometry and expanded as five clone lines derived from a single cell. All clone lines demonstrated expression of both hepatocyte and cholangiocyte markers and maintained a small population (0.5% to 2%) of CD133+ cells in vitro, and three of five clone lines produced tumors. Although TGF-β1 inhibited cell growth equally in CD133%- and CD133+ cells from each clone line, the CD133+ population demonstrated significant resistance to TGF-β-induced apoptosis compared with CD133- cells. Furthermore, CD133+ cells demonstrated a substantial increase in mitogenactivated protein kinase (MAPK) pathway activation, as demonstrated by phosphorylated extracellular signal-regulated kinase levels before and after TGF-β stimulation. MAPK inhibition using mitogen-activated protein kinase kinase 1 (MEK1) inhibitor PD98059 led to a significant increase in TGF-β-induced apoptosis in CD133+ cells. Conversely, a constitutively active form of MEK1 blocked the apoptotic effects of TGF-β in CD133- cells. Conclusion: CD133± liver cancer stem cells exhibit relative resistance to TGF-β-induced apoptosis. One mechanism of resistance to TGF-β-induced apoptosis in CD133+ cancer stem cells is an activated mitogenactivated protein kinase/extracellular signal-regulated kinase pathway.

Original languageEnglish (US)
Pages (from-to)1277-1286
Number of pages10
JournalHepatology
Volume49
Issue number4
DOIs
StatePublished - Jun 24 2009

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Neoplastic Stem Cells
Transforming Growth Factors
Liver Neoplasms
Transferases
Methionine
Apoptosis
Clone Cells
Methionine Adenosyltransferase
Protein Kinases
Extracellular Signal-Regulated MAP Kinases
Liver
MAP Kinase Kinase 1
Population
S-Adenosylmethionine
Hepatocytes
Hepatocellular Carcinoma
Flow Cytometry
Carcinogenesis
Stem Cells
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Ding, Wei ; Mouzaki, Marialena ; You, Hanning ; Laird, Joshua C. ; Mato, Jose ; Lu, Shelly C. ; Rountree, C. Bart. / CD133+ liver cancer stem cells from methionine adenosyl transferase 1A-deficient mice demonstrate resistance to transforming growth factor (TGF)-β-induced apoptosis. In: Hepatology. 2009 ; Vol. 49, No. 4. pp. 1277-1286.
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title = "CD133+ liver cancer stem cells from methionine adenosyl transferase 1A-deficient mice demonstrate resistance to transforming growth factor (TGF)-β-induced apoptosis",
abstract = "Methionine adenosyltransferase (MAT) is an essential enzyme required for S-adenosylmethionine biosynthesis. Hepatic MAT activity falls during chronic liver injury, and mice lacking Mat1a develop spontaneous hepatocellular carcinoma by 18 months. We have previously demonstrated that CD133+CD45- oval cells isolated from 16-month-old Mat1a-/- mice represent a liver cancer stem cell population. The transforming growth factor β (TGF-β) pathway constitutes a central signaling network in proliferation, apoptosis, and tumorigenesis. In this study, we tested the response of tumorigenic liver stem cells to TGF-β. CD133+CD45- oval cells were isolated from premalignant 16-month-old Mat1a-/- mice by flow cytometry and expanded as five clone lines derived from a single cell. All clone lines demonstrated expression of both hepatocyte and cholangiocyte markers and maintained a small population (0.5{\%} to 2{\%}) of CD133+ cells in vitro, and three of five clone lines produced tumors. Although TGF-β1 inhibited cell growth equally in CD133{\%}- and CD133+ cells from each clone line, the CD133+ population demonstrated significant resistance to TGF-β-induced apoptosis compared with CD133- cells. Furthermore, CD133+ cells demonstrated a substantial increase in mitogenactivated protein kinase (MAPK) pathway activation, as demonstrated by phosphorylated extracellular signal-regulated kinase levels before and after TGF-β stimulation. MAPK inhibition using mitogen-activated protein kinase kinase 1 (MEK1) inhibitor PD98059 led to a significant increase in TGF-β-induced apoptosis in CD133+ cells. Conversely, a constitutively active form of MEK1 blocked the apoptotic effects of TGF-β in CD133- cells. Conclusion: CD133± liver cancer stem cells exhibit relative resistance to TGF-β-induced apoptosis. One mechanism of resistance to TGF-β-induced apoptosis in CD133+ cancer stem cells is an activated mitogenactivated protein kinase/extracellular signal-regulated kinase pathway.",
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CD133+ liver cancer stem cells from methionine adenosyl transferase 1A-deficient mice demonstrate resistance to transforming growth factor (TGF)-β-induced apoptosis. / Ding, Wei; Mouzaki, Marialena; You, Hanning; Laird, Joshua C.; Mato, Jose; Lu, Shelly C.; Rountree, C. Bart.

In: Hepatology, Vol. 49, No. 4, 24.06.2009, p. 1277-1286.

Research output: Contribution to journalArticle

TY - JOUR

T1 - CD133+ liver cancer stem cells from methionine adenosyl transferase 1A-deficient mice demonstrate resistance to transforming growth factor (TGF)-β-induced apoptosis

AU - Ding, Wei

AU - Mouzaki, Marialena

AU - You, Hanning

AU - Laird, Joshua C.

AU - Mato, Jose

AU - Lu, Shelly C.

AU - Rountree, C. Bart

PY - 2009/6/24

Y1 - 2009/6/24

N2 - Methionine adenosyltransferase (MAT) is an essential enzyme required for S-adenosylmethionine biosynthesis. Hepatic MAT activity falls during chronic liver injury, and mice lacking Mat1a develop spontaneous hepatocellular carcinoma by 18 months. We have previously demonstrated that CD133+CD45- oval cells isolated from 16-month-old Mat1a-/- mice represent a liver cancer stem cell population. The transforming growth factor β (TGF-β) pathway constitutes a central signaling network in proliferation, apoptosis, and tumorigenesis. In this study, we tested the response of tumorigenic liver stem cells to TGF-β. CD133+CD45- oval cells were isolated from premalignant 16-month-old Mat1a-/- mice by flow cytometry and expanded as five clone lines derived from a single cell. All clone lines demonstrated expression of both hepatocyte and cholangiocyte markers and maintained a small population (0.5% to 2%) of CD133+ cells in vitro, and three of five clone lines produced tumors. Although TGF-β1 inhibited cell growth equally in CD133%- and CD133+ cells from each clone line, the CD133+ population demonstrated significant resistance to TGF-β-induced apoptosis compared with CD133- cells. Furthermore, CD133+ cells demonstrated a substantial increase in mitogenactivated protein kinase (MAPK) pathway activation, as demonstrated by phosphorylated extracellular signal-regulated kinase levels before and after TGF-β stimulation. MAPK inhibition using mitogen-activated protein kinase kinase 1 (MEK1) inhibitor PD98059 led to a significant increase in TGF-β-induced apoptosis in CD133+ cells. Conversely, a constitutively active form of MEK1 blocked the apoptotic effects of TGF-β in CD133- cells. Conclusion: CD133± liver cancer stem cells exhibit relative resistance to TGF-β-induced apoptosis. One mechanism of resistance to TGF-β-induced apoptosis in CD133+ cancer stem cells is an activated mitogenactivated protein kinase/extracellular signal-regulated kinase pathway.

AB - Methionine adenosyltransferase (MAT) is an essential enzyme required for S-adenosylmethionine biosynthesis. Hepatic MAT activity falls during chronic liver injury, and mice lacking Mat1a develop spontaneous hepatocellular carcinoma by 18 months. We have previously demonstrated that CD133+CD45- oval cells isolated from 16-month-old Mat1a-/- mice represent a liver cancer stem cell population. The transforming growth factor β (TGF-β) pathway constitutes a central signaling network in proliferation, apoptosis, and tumorigenesis. In this study, we tested the response of tumorigenic liver stem cells to TGF-β. CD133+CD45- oval cells were isolated from premalignant 16-month-old Mat1a-/- mice by flow cytometry and expanded as five clone lines derived from a single cell. All clone lines demonstrated expression of both hepatocyte and cholangiocyte markers and maintained a small population (0.5% to 2%) of CD133+ cells in vitro, and three of five clone lines produced tumors. Although TGF-β1 inhibited cell growth equally in CD133%- and CD133+ cells from each clone line, the CD133+ population demonstrated significant resistance to TGF-β-induced apoptosis compared with CD133- cells. Furthermore, CD133+ cells demonstrated a substantial increase in mitogenactivated protein kinase (MAPK) pathway activation, as demonstrated by phosphorylated extracellular signal-regulated kinase levels before and after TGF-β stimulation. MAPK inhibition using mitogen-activated protein kinase kinase 1 (MEK1) inhibitor PD98059 led to a significant increase in TGF-β-induced apoptosis in CD133+ cells. Conversely, a constitutively active form of MEK1 blocked the apoptotic effects of TGF-β in CD133- cells. Conclusion: CD133± liver cancer stem cells exhibit relative resistance to TGF-β-induced apoptosis. One mechanism of resistance to TGF-β-induced apoptosis in CD133+ cancer stem cells is an activated mitogenactivated protein kinase/extracellular signal-regulated kinase pathway.

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