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Decreased expression of cystathionine ?-synthase promotes glioma tumorigenesis.

ABSTRACT: Cystathionine ?-synthase (CBS) catalyzes metabolic reactions that convert homocysteine to cystathionine. To assess the role of CBS in human glioma, cells were stably transfected with lentiviral vectors encoding shRNA targeting CBS or a nontargeting control shRNA, and subclones were injected into immunodeficient mice. Interestingly, decreased CBS expression did not affect proliferation in vitro but decreased the latency period before rapid tumor xenograft growth after subcutaneous injection and increased tumor incidence and volume following orthotopic implantation into the caudate-putamen. In soft-agar colony formation assays, CBS knockdown subclones displayed increased anchorage-independent growth. Molecular analysis revealed that CBS knockdown subclones expressed higher basal levels of the transcriptional activator hypoxia-inducible factor 2? (HIF2?/EPAS1). HIF2? knockdown counteracted the effect of CBS knockdown on anchorage-independent growth. Bioinformatic analysis of mRNA expression data from human glioma specimens revealed a significant association between low expression of CBS mRNA and high expression of angiopoietin-like 4 (ANGPTL4) and VEGF transcripts, which are HIF2 target gene products that were also increased in CBS knockdown subclones. These results suggest that decreased CBS expression in glioma increases HIF2? protein levels and HIF2 target gene expression, which promotes glioma tumor formation.CBS loss-of-function promotes glioma growth.

SUBMITTER: Takano N

PROVIDER: S-EPMC4274393 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Decreased expression of cystathionine β-synthase promotes glioma tumorigenesis.

Takano Naoharu N Sarfraz Yasmeen Y Gilkes Daniele M DM Chaturvedi Pallavi P Xiang Lisha L Suematsu Makoto M Zagzag David D Semenza Gregg L GL

Molecular cancer research : MCR 20140703 10

<h4>Unlabelled</h4>Cystathionine β-synthase (CBS) catalyzes metabolic reactions that convert homocysteine to cystathionine. To assess the role of CBS in human glioma, cells were stably transfected with lentiviral vectors encoding shRNA targeting CBS or a nontargeting control shRNA, and subclones were injected into immunodeficient mice. Interestingly, decreased CBS expression did not affect proliferation in vitro but decreased the latency period before rapid tumor xenograft growth after subcutane ...[more]

PMID: 24994751

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Project description:BACKGROUND:SOX2 is regarded as an important marker in stem cell. The change of SOX2 expression after adjuvant therapy in high grade glioma (HGG) remains unknown so far. Few patients with recurrent glioma have opportunity to undergo operation once again, so the recurrent glioma samples are scarce. This study tries to analyze SOX2 expression in paired primary and recurrent HGG, aims to better understand the transformation law of SOX2 after adjuvant therapy in HGG. METHODS:Twenty-four recurrent HGG patients who undergone a second resection were included. 16 patients received adjuvant therapy, the remaining 8 patients didn't receive any adjuvant therapy at all. The protein expression of SOX2 in paired primary and recurrent HGG was tested by immunohistochemistry. The statistical analysis was conducted by IBM SPSS Statistics 19.0. RESULTS:In primary HGG, SOX2 expression of 3?+?, 2?+?, 1+ and 0+ were seen in 20 (83.3%), 1 (4.2%), 1 (4.2%) and 2 cases (8.3%), respectively. The expression of SOX2 was decreased in recurrent HGG compared to the paired primary sample (p?=?0.001). The decrease of SOX2 was often seen in patients received chemotherapy, radiotherapy or both (p?=?0.003). Patients with SOX2 high expression in primary glioma had a longer median PFS than those with SOX2 low expression with marginal statistic significance (12.7 vs. 5.4?months, p?=?0.083). For cases with SOX2 high expression in the primary glioma, those had SOX2 low expression after recurrence seemed to have worse prognosis as compared to patients with stable SOX2 high expression (PFS: 10.4 vs. 14.9?months, p?=?0.036; OS: 27.0 vs 49.5?months, p?=?0.005). CONCLUSIONS:This is the first study comparing the protein expression of SOX2 in recurrent HGG and its paired primary tumor. SOX2 high expression is common in brain HGG, a tendency of decreased SOX2 expression in recurrent gliomas was evidenced. Lower SOX2 expression was seen in those patients who received adjuvant chemotherapy and/or radiotherapy. Patients with low SOX2 expression in primary HGG usually have poorer prognosis, those with SOX2 expression decreased in recurrent HGG had worse outcome.

Dataset Information

Decreased expression of cystathionine ?-synthase promotes glioma tumorigenesis.

Publications

Decreased expression of cystathionine β-synthase promotes glioma tumorigenesis.

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