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CD133+ liver cancer stem cells from methionine adenosyl transferase 1A-deficient mice demonstrate resistance to transforming growth factor (TGF)-beta-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 beta (TGF-beta) 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-beta. 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-beta1 inhibited cell growth equally in CD133(-) and CD133(+) cells from each clone line, the CD133(+) population demonstrated significant resistance to TGF-beta-induced apoptosis compared with CD133(-) cells. Furthermore, CD133(+) cells demonstrated a substantial increase in mitogen-activated protein kinase (MAPK) pathway activation, as demonstrated by phosphorylated extracellular signal-regulated kinase levels before and after TGF-beta stimulation. MAPK inhibition using mitogen-activated protein kinase kinase 1 (MEK1) inhibitor PD98059 led to a significant increase in TGF-beta-induced apoptosis in CD133(+) cells. Conversely, a constitutively active form of MEK1 blocked the apoptotic effects of TGF-beta in CD133(-) cells.CD133(+) liver cancer stem cells exhibit relative resistance to TGF-beta-induced apoptosis. One mechanism of resistance to TGF-beta-induced apoptosis in CD133(+) cancer stem cells is an activated mitogen-activated protein kinase/extracellular signal-regulated kinase pathway.

SUBMITTER: Ding W

PROVIDER: S-EPMC2853874 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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

Ding Wei W Mouzaki Marialena M You Hanning H Laird Joshua C JC Mato Jose J Lu Shelly C SC Rountree C Bart CB

Hepatology (Baltimore, Md.) 20090401 4

<h4>Unlabelled</h4>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 beta (TGF-beta) pathway constitutes a central sign ...[more]

PMID: 19115422

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Project description:Methionine adenosyl transferases (MATs) catalyze the synthesis of the biological methyl donor adenosylmethionine (SAM). Dysregulation of MATs has been associated with carcinogenesis in humans. We previously found that downregulation of the MAT1A gene enriches the protein-associated translation process and worsens liver hepatocellular carcinoma (LIHC) prognosis. We also discovered that subcellular localization of the MAT2A protein has independently prognostic relevance in breast cancer patients. The present study aimed to examined the clinical relevance of MAT2A translocation in human LIHC. Essential methionine cycle gene expressions in TCGA LIHC datasets were analyzed using Gene Expression Profiling Interactive Analysis 2 (GEPIA2). The protein expression pattern of MAT2A was determined in the tissue array of our own LIHC cohort (n = 261) using immuno-histochemistry, and the prognostic relevance of MAT2A protein's subcellular localization expression was examined using Kaplan-Meier survival curves. LIHC patients with higher MAT2A mRNA expression had a worse survival rate (p = 0.0083). MAT2A protein immunoreactivity was observed in both cytoplasm and nucleus fractions in the tissue array. Tumor tissues had elevated MAT2A protein expression in both cytoplasm and nucleus compared to their adjacent normal tissues. A higher cytoplasmic to nuclear MAT2A protein expression ratio (C/N) was found in female LIHC patients compared to that of male patients (p = 0.047). Kaplan-Meier survival curves showed that a lower MAT2A C/N correlated with poor overall survival in female LIHC patients (10-year survival rate: 29.2% vs. 68.8%, C/N ≤ 1.0 vs. C/N > 1.0, log-rank p = 0.004). Moreover, we found that specificity protein 1 (SP1) may have a potential interaction with nuclear MAT2A protein, using protein-protein interaction; this we found using the GeneMANIA algorithm. We explored the possible protective effects of the estrogen axis in LIHC using the Human Protein Atlas (HPA), and found evidence supporting a possible protective effect of estrogen-related protein ESSRG in LIHC. The localization of SP1 and MAT2 appeared to be inversely associated with ESRRG expression in LIHC. The present study demonstrated the translocation of MAT2A and its prognostic relevance in female LIHC patients. Our findings suggest the potential of estrogen in SP1 regulation and localization of MAT2A, as therapeutic modalities against in female LIHC patients.

Dataset Information

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

Publications

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

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