Some colorectal cancers arise from a field defect defined by epigenetic inactivation of MGMT. Detection of this abnormality may ultimately be useful in risk assessment for colorectal cancer.

No abstract

We conducted a phase 1/2 study of the combination of 5-aza-2-deoxycytidine (decitabine) and the histone deacetylase inhibitor valproic acid (VPA) in patients with advanced leukemia, including older untreated patients. A group of 54 patients were treated with a fixed dose of decitabine (15 mg/m 2 by IV daily for 10 days) administered concomitantly with escalating doses of VPA orally for 10 days. A 50 mg/kg daily dose of VPA was found to be safe. Twelve (

Arsenic trioxide (As 2 O 3 ) has shown considerable efficacy in treating hematological malignancies with induction of programmed cell death (PCD) type I, apoptosis. However, the mechanisms underlying the antitumor effect of As 2 O 3 on solid tumors are poorly defined. Previously, we reported that As 2 O 3 induced autophagic cell death (PCD type II) but not apoptosis in human malignant glioma cell lines. The purpose of this study was to elucidate the molecular pathway leading to autophagic cell death. In this study, we demonstrated that the cell death was accompanied by involvement of autophagy-specific marker, microtubule-associated protein light chain 3 (LC3), and damage of mitochondrial membrane integrity, but not by caspase activation. Analysis by cDNA microarray, RT-PCR, and Western blot showed that cell death members of Bcl-2 family, Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3) and its homologue BNIP3-like (BNIP3L), were upregulated in As 2 O 3 -induced autophagic cell death. Exogenous expression of BNIP3, but not BNIP3L, induced autophagic cell death in malignant glioma cells without As 2 O 3 treatment. When upregulation of BNIP3 induced by As 2 O 3 was suppressed by a dominant-negative effect of the transmembranedeleted BNIP3 (BNIP3DTM), autophagic cell death was inhibited. In contrast, BNIP3 transfection augmented As 2 O 3 -induced autophagic cell death. These results suggest that BNIP3 plays a central role in As 2 O 3 -induced autophagic cell death in malignant glioma cells. This study adds a new concept to characterize the pathways by which As 2 O 3 acts to induce autophagic cell death in malignant glioma cells. Oncogene (2005) 24, 980-991.

Single-nucleotide polymorphisms (SNP) associated with polygenetic disorders, such as breast cancer (BC), can create, destroy, or modify microRNA (miRNA) binding sites; however, the extent to which SNPs interfere with miRNA gene regulation and affect cancer susceptibility remains largely unknown. We hypothesize that disruption of miRNA target binding by SNPs is a widespread mechanism relevant to cancer susceptibility. To test this, we analyzed SNPs known to be associated with BC risk, in silico and in vitro, for their ability to modify miRNA binding sites and miRNA gene regulation and referred to these as target SNPs. We identified rs1982073-TGFB1 and rs1799782-XRCC1 as target SNPs, whose alleles could modulate gene expression by differential interaction with miR-187 and miR-138, respectively. Genome-wide bioinformatics analysis predicted ∼64% of transcribed SNPs as target SNPs that can modify (increase/decrease) the binding energy of putative miRNA::mRNA duplexes by >90%. To assess whether target SNPs are implicated in BC susceptibility, we conducted a case-control population study and observed that germline occurrence of rs799917-BRCA1 and rs334348-TGFR1 significantly varies among populations with different risks of developing BC. Luciferase activity of target SNPs, allelic variants, and protein levels in cancer cell lines with different genotypes showed differential regulation of target genes following overexpression of the two interacting miRNAs (miR-638 and miR-628-5p). Therefore, we propose that transcribed target SNPs alter miRNA gene regulation and, consequently, protein expression, contributing to the likelihood of cancer susceptibility, by a novel mechanism of subtle gene regulation. Cancer Res; 70(7); 2789-98. ©2010 AACR.