The important role of GATA3 in endothelial cells of large vessels

Song Hai Hua, a graduate student (currently working for a Chinese company) and her colleagues in the Vascular Research Division of LSBM investigated GATA transcription factors  GATA2, 3, and 6 that are expressed in endothelial cells. They found that only GATA2 was expressed in microvessel where as the expression of GATA3 was highest in large blood vessels. They also found that GATA3 plays a critical role in mediating Tie2 expression.  They concluded that GATA3 contributes to cell migration, inhibition of inflammation, and inhibition of apoptosis mediated by Angiopoietin-Tie2 signaling in endothelial cells.

Song H, Suehiro J, Kanki Y, Kawai Y, Inoue K, Daida H, Yano K, Ohhashi T, Oettgen P, Aird WC, Kodama T, Minami T.
Critical role for GATA3 in mediating Tie2 expression and function in large vessel endothelial cells.
J Biol Chem. 2009 Oct 16;284(42):29109-24. Epub 2009 Aug 12.

Discovery of the major factors of endothelial cell activation

Endothelial cell activation is a key factor contributing to homeostasis of vascular system.  In a pathological environment, the activation causes malfunction of the endothelial cells and facilitates inflammation, atherosclerosis, and tumor progression which form the basis for metabolic syndrome diseases. Graduate students of the LSBM vascular research group, Dr. Junichi Suehiro (currently Project Research Fellow at LSBM) and his colleagues investigated key regulators in endothelial cell activation. They conducted transcriptome analysis using umbilical-vein-endothelial cells stimulated by VEGF, Thrombin, or TNF- α  They found  that Egr-1 and Egr-3, the family of early growth response< (EGR) transcription factors, were induced during endothelial activation process.  In particular, EGR-3 plays a major role in endothelial activation (multiplication, migration, tube formation, and monocyte adhesion) mediated by VEGF.  They found that pathological angiogenesis and solid tumor progression can be inhibited by suppressing the EGR-3 expression in mice. 

Blood. 2009 Nov 23.
Vascular endothelial growth factor activation of endothelial cells is mediated by early growth response-3.
Suehiro JI, Hamakubo T, Kodama T, Aird WC, Minami T.

Identified three epigenome types in human colorectal cancer

In Genome Science Division, a group of a senior graduate student Koichi Yagi, Associate Professor Dr. Atsushi Kaneda, and others indentified three different epigenome types in human colorectal cancer through a whole genome DNA methylation analysis. The study was published in Journal of  Clinical Cancer Research. (published online 22 Dec 2009).

An accumulation of both genetic and epigenetic abnormalities are closely related to the occurrence of cancer. For example, IGF2 LOI mouse whose IGF2 genetic imprinting has disappeared,  which represents one of the abnormal epigenotypes, has a two-fold greater risk of developing an intestinal tumor crossing with Min mouse which has mutation in APC gene, or by administration of an carcinogenic compound, Azoxymethane.

In this research, they analyzed DNA methylation as epigenetic marker of colorectal cancer. First, all genes with methlated promoter-region were extracted by the MeDIP-chip method from several colorectal cancer cell-lines.  The expression silencing and expression recovery from demethylation were performed by an expression array analysis and 44 methylated markers were isolated. The methylation status of 60 regions, including previous 16 markers were quantitatively analysed by mass spectrometry using MALDI-TOF MS (Mass ARRAY). 149 colorectal cancer samples were classified into three epigenomic types by two-way hierarchical clustering used for methylation markers. In addition to the DNA methylation analysis, they also investigated BRAF or KRAS oncogenic mutations, p53 immunostaining, and microsatellite instability.

A significant correlation was observed for each of the hyper-methylation and mutation s in BRAF gene and also the intermediate methylation and mutations in KRAS gene. These results suggested different molecular mechanisms for the occurrence of colon cancer depending on the methylation level.  Since intermediate methylation cases with KRAS mutation demonstrated a significantly poor prognosis, this epigenotyping will have clinical importance

Koichi Yagi, Kiwamu Akagi, Hiroshi Hayashi, Genta Nagae, Shingo Tsuji, Takayuki Isagawa, Yutaka Midorikawa, Yoji Nishimura, Hirohiko Sakamoto, Yasuyuki Seto, Hiroyuki Aburatani, & Atsushi Kaneda.
Three DNA methylation epigenotypes in human colorectal cancer.
Clin Cancer Res. Published Online (December 22, 2009), doi:10.1158/1078-0432.CCR-09-2006

This article of colorectal cancer epigenotype has been selected for the Research Highlights in Journal of Clinical Cancer Research.

The article on colorectal cancer epigenome type that had been reported on 12/22 last year with an online version by graduate student, Koichi Yagi and others has been selected for Research Highlights in the Journal of Clinical Cancer Research published in 2010/1/1. The importance of the comprehensive analysis that demonstrated the relation of DNA methylation epigenotypes with BRAF mutation or KRAS mutation was highly recognized in the journal.

The study strongly indicated the importance of the development of DNA methylation markers to predict the prognosis of colorectal cancer , which is encouraging for all researchers in the field..

Highlights of This Issue.
Clin Cancer Res; 16(1):vii, 2010.
Koichi Yagi, Kiwamu Akagi, Hiroshi Hayashi, Genta Nagae, Shingo Tsuji, Takayuki Isagawa, Yutaka Midorikawa, Yoji Nishimura, Hirohiko Sakamoto, Yasuyuki Seto, Hiroyuki Aburatani, & Atsushi Kaneda.
Three DNA methylation epigenotypes in human colorectal cancer.
Clin Cancer Res; 16(1):21-33, 2010