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Medical Sciences	100%

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DNA methylation and histone modifications cause silencing of Wnt antagonist gene in human renal cell carcinoma cell lines

INTERNATIONAL JOURNAL OF CANCER, Issue 3 2008
Ken Kawamoto
Abstract Secreted frizzled-related protein 2 (sFRP2) is a negative modulator of the Wingless-type (Wnt) signaling pathway, and shown to be inactivated in renal cell carcinoma (RCC). However, the molecular mechanism of silencing of sFRP2 is not fully understood. Our study was designed to elucidate the silencing mechanism of sFRP2 in RCC. Expression of sFRP2 was examined in 20 pairs of primary cancers by immunohistochemistry. Kidney cell lines (HK-2, Caki-1, Caki-2, A-498 and ACHN) were analyzed for sFRP2 expression using real-time RT-PCR and Western blotting. The methylation status at 46 CpG sites of the 2 CpG islands in the sFRP2 promoter was characterized by bisulfite DNA sequencing. Histone modifications were assessed by chromatin immunoprecipitation (ChIP) assay using antibodies against AcH3, AcH4, H3K4 and H3K9. sFRP2 was frequently repressed in primary cancers and in RCC cells. The majority of sFRP2 negative cells had a methylated promoter. Meanwhile, sFRP2 expression was repressed by a hypomethylated promoter in Caki-1 cells, and these cells had a repressive histone modification at the promoter. In Caki-1 cells, sFRP2 was reactivated by trichostatin A (TSA). Repressive histone modifications were also observed in RCC cells with hypermethylated promoters, but sFRP2 was reactivated only by 5-aza-2,-deoxycytidine (DAC) and not by TSA. However, the activation of the silenced sFRP2 gene could be achieved in all cells using a combination of DAC and TSA. This is the first report indicating that aberrant DNA methylation and histone modifications work together to silence the sFRP2 gene in RCC cells. © 2008 Wiley-Liss, Inc. [source]

Aggressive progression of breast cancer with microscopic pulmonary emboli possessing a stem cell-like phenotype independent of its origin

PATHOLOGY INTERNATIONAL, Issue 3 2010
Hideya Kawasaki
Microscopic pulmonary tumor embolism is difficult to diagnose. Herein is presented the case of a patient who suffered from acute dyspnea and breast cancer on the right side. Two weeks after the breast cancer diagnosis the patient began to experience dyspnea. After 2 weeks of dyspnea, the patient died without an accurate diagnosis of dyspnea. Autopsy indicated massive microscopic pulmonary emboli of the breast cancer. Immunohistochemistry showed that most of the cancer cells in the primary site were negative for estrogen receptors, progesterone receptors Her2/neu oncogene (triple negative), and stem cell-like markers (OCT3/4, NANOG2, CD44, CD24, aldehyde dehydrogenase 1 (ALDH1)). The breast cancer cells in the lung (the metastasized site), however, were triple negative, but were enriched in stem cell-like markers (OCT3/4+, NANOG2+, CD44+/CD24,/low, ALDH1+). This is a significant case report indicating that vascular emboli themselves contain the essential molecular signature of ,stemness' independent of the origin. [source]

Happiness and Stress Alter Susceptibility to Cardiac Events in Long QT Syndrome

ANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 2 2009
Ph.D., Richard D. Lane M.D.
Objective: We sought to determine whether the circumstances preceding an arrhythmic event differed from those preceding a prior control occasion in patients with Long QT Syndrome (LQTS), a well-characterized genetic disorder that puts affected individuals at risk for sudden cardiac death. Methods: Thirty-eight patients (89% female) with LQTS completed a "case-crossover interview" in which each patient served as his/her own control by reporting on circumstances preceding an arrhythmic event (syncope, aborted cardiac arrest, or defibrillator discharge) and preceding a control occasion (the next-to-last birthday). On average the interview was conducted 17 months after the cardiac event and control occasion. Results: During the 24-hour period preceding the cardiac event compared to the day before the control occasion, psychological stress was elevated, peak happiness was reduced, and peak exertion was not significantly different. Rated for the 6-month intervals preceding the event and control occasions, none of these three variables was significantly associated with events. Conclusions: Happiness is associated with a reduction in the 24-hour risk of cardiac events in patients with LQTS, with stress having an opposite effect. To our knowledge, this is the first report indicating that positive emotion may have a protective effect on life-threatening ventricular arrhythmias. This study lends further support to the role of emotions in influencing cardiac events in arrhythmia-prone patients. [source]

(,)-Epigallocatechin-3-gallate induces Du145 prostate cancer cell death via downregulation of inhibitor of DNA binding 2, a dominant negative helix-loop-helix protein

CANCER SCIENCE, Issue 3 2010
Katherine L. Luo
(Cancer Sci 2010; 101: 707,712) (,)-Epigallocatechin-3-gallate (EGCG) is one of the major polyphenol components in green tea. It effectively induces apoptosis in prostate cancer cells. The anticancer effect of this reagent is appealing because it is a natural component of a popular daily beverage that has proven harmless for thousands of years, making it a good candidate chemopreventive agent. EGCG suppresses cell growth and causes cell death, but the mechanisms are not well characterized, especially in androgen-independent prostate cancer cells. In the present study, using Affymetrix genechip Hu133 2.0, we analyzed the gene expression patterns of the androgen-independent prostate cancer cell line Du145, treated with or without EGCG, and found 40 genes whose expression levels were altered (>twofold, either upregulated or downregulated, P < 0.01) upon treatment with EGCG. These gene products are involved in the functions of transcription, RNA processing, protein folding, phosphorylation, protein degradation, cell motility, and ion transport. Among them, inhibitor of DNA binding 2 (ID2), known as a dominant anti-retinoblastoma (Rb) helix-loop-helix protein, was found to be downregulated fourfold by EGCG treatment. Forced expression of ID2 in Du145 cells reduced apoptosis and increased cell survival in the presence of EGCG, and knockdown ID2 expression in Du145 cells using a morpholino oligonucleotide specific for ID2 mimicked the apoptosis effect generated by EGCG treatment, although it was milder. To our knowledge, this is the first report indicating that ID2 is one of the critical factors in the signaling pathway of Du145 cell death induced by EGCG. [source]