Genome-Wide Association Study in East Asians Identifies Novel Susceptibility Loci for Breast Cancer

Long, Jirong,Cai, Qiuyin,Sung, Hyuna,Shi, Jiajun,Zhang, Ben,Choi, Ji-Yeob,Wen, Wanqing,Delahanty, Ryan J.,Lu, Wei,Gao, Yu-Tang,Shen, Hongbing,Park, Sue K.,Chen, Kexin,Shen, Chen-Yang,Ren, Zefang,Haima Public Library of Science 2012 PLoS genetics Vol.8 No.2

<P>Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage genome-wide association study (GWAS) in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls). SNP rs9485372, near the TGF-β activated kinase (<I>TAB2</I>) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a <I>P</I>-value of 3.8×10<SUP>−12</SUP> in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85–0.94) and 0.80 (0.75–0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (<I>P</I> = 1.9×10<SUP>−6</SUP> from the combined analysis of all samples), located in intron 5 of the <I>ESR1</I> gene, and SNP rs7107217 (<I>P</I> = 4.6×10<SUP>−7</SUP>), located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the <I>TAB2</I> gene (6q25.1), and identifies two possible susceptibility loci located in the <I>ESR1</I> gene and 11q24.3, respectively.</P><P><B>Author Summary</B></P> <P>Breast cancer is one of the most common malignancies among women worldwide. Genetic factors play an important role in the etiology of breast cancer. To identify common genetic susceptibility alleles for breast cancer, we performed a four-stage genome-wide association study in 19,091 cases and 20,606 controls among East-Asian women. Single nucleotide polymorphism (SNP) rs9485372, near the TGF-beta activated kinase 1 (<I>TAB2</I>) gene at chromosome 6q25.1, was associated with breast cancer risk (<I>P</I> = 3.8×10<SUP>−12</SUP>). SNPs rs9383951, located in intron 5 of the estrogen receptor 1 (<I>ESR1</I>) gene, and rs7107217, located at 11q24.3, were also consistently associated with breast cancer risk in all four stages with a combined <I>P</I> of 1.9×10<SUP>−6</SUP> and 4.6×10<SUP>−7</SUP>, respectively. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the <I>TAB2</I> gene (6q25.1), and identifies two possible susceptibility loci located in the <I>ESR1</I> gene and 11q24.3, respectively.</P>

CTLA4-Ig protects tacrolimus-induced oxidative stress via inhibiting the AKT/FOXO3 signaling pathway in rats

Long Jin,Nan Shen,Xinyu Wen,Weidong Wang,Sun Woo Lim,양철우 대한내과학회 2023 The Korean Journal of Internal Medicine Vol.38 No.3

Background/Aims: Although the conversion from tacrolimus (TAC) to cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (CTLA4-Ig) is effective in reducing TAC-induced nephrotoxicity, it remains unclear whether CTLA4-Ig has a direct effect on TAC-induced renal injury. In this study, we evaluated the effects of CTLA4-Ig on TAC-induced renal injury in terms of oxidative stress. Methods: In vitro study was performed to assess the effect of CTLA4-Ig on TAC-induced cell death, reactive oxygen species (ROS), apoptosis, and the protein kinase B (AKT)/forkhead transcription factor (FOXO) 3 pathway in human kidney 2 cells. In the in vivo study, the effect of CTLA4-Ig on TAC-induced renal injury was evaluated using renal function, histopathology, markers of oxidative stress (8-hydroxy-2’-deoxyguanosine) and metabolites (4-hydroxy-2-hexenal, catalase, glutathione S-transferase, and glutathione reductase), and activation of the AKT/FOXO3 pathway with insulin-like growth factor 1 (IGF-1). Results: CTLA4-Ig significantly decreased cell death, ROS, and apoptosis caused by TAC. TAC treatment increased apoptotic cell death and apoptosis-related proteins (increased Bcl-2-associated X protein and caspase-3 and decreased Bcl-2), but it was reversed by CTLA4-Ig treatment. The activation of p-AKT and p-FOXO3 by TAC decreased with CTLA4-Ig treatment. TAC-induced renal dysfunction and oxidative marker levels were significantly improved by CTLA4-Ig in vivo. Concomitant IGF- 1 treatment abolished the effects of CTLA4-Ig. Conclusions: CTLA4-Ig has a direct protective effect on TAC-induced renal injury via the inhibition of AKT/FOXO3 pathway.

Lycorine: A Potential Broad-Spectrum Agent Against Crop Pathogenic Fungi

( Jin Wen Shen ),( Yuan Ruan ),( Wei Ren ),( Bing Ji Ma ),( Xiao Long Wang ),( Chun Feng Zheng ) 한국미생물 · 생명공학회 2014 Journal of microbiology and biotechnology Vol.24 No.3

A screening test showed that lycorine exhibited significant antifungal activity against 24 pathogenic crop fungi at concentrations of 500μg/ml and 100μg/ml, respectively. Fusarium graminearum was selected for antifungal mechanism studies by observing its mycelial morphology and investigating the variations in its conductivity. In addition, the substance absorption and metabolism of F. graminearum were explored. The mechanism was revealed as being one by which lycorine destroyed the cellular membrane and further influenced substance absorption and cell metabolism.

SEPT12 Interacts with SEPT6 and This Interaction Alters the Filament Structure of SEPT6 in Hela Cells

( Xiang Ming Ding ),( Wen Bo Yu ),( Ming Liu ),( Su Qin Shen ),( Fang Chen ),( Bo Wan ),( Long Yu ) 생화학분자생물학회 2007 BMB Reports Vol.40 No.6

Chlorophyll Fluorescence Characteristics and Rapid Light Response Curves of Alpine Rhododendron

Yuan-Huan Liu,Fang-Li Liu,Bo Long,Xiong-Li Zhou,Xue Zhang,Yue Zhang,Wen-Li Wang,Shi-Kang Shen 한국원예학회 2019 원예과학기술지 Vol.37 No.4

The aim of this study was to determine the photosynthetic adaptability of Rhododendron species toalpine environments. The chlorophyll fluorescence parameters and rapid light response curves ofeight Rhododendron species were determined under field conditions across elevation gradients (atelevations of 2,950, 3,560, 3,660, 3,770, and 4,030 m) in the Jiaozi Mountain National NaturalReserve, Yunnan Province, southwestern China. The effect of different elevations, species, and theirinteractions significantly affected most of the chlorophyll fluorescence and rapid light response curveparameters. The variable to maximum fluorescence ratio (Fv/Fm) ranged from 0.78 to 0.81 at the fiveelevation gradients. This result indicated that the studied species were well grown and adapted to thecurrent environment. The correlation analysis indicated that the elevation was positively significantlycorrelated with the photochemical efficiency of photosystem II, electron transport rate, maximumelectron transport rate, light saturation coefficient (Ek), and chlorophyll relative content (SPAD: leafchlorophyll content index) and was negatively significantly correlated with photochemicalquenching, nonphotochemical quenching, and linear initial slope values. Although no significantrelationship was observed between the elevations and Fv/Fm, the apparent difference in Fv/Fm both atelevation gradients and elevation × species levels indicated that the Rhododendron speciesdemonstrated species-specific adaptation to the environment at different elevations. Our resultsprovided evidence that Rhododendron species exhibit variations in photosynthetic activities in analpine environment at different elevations. These differences may improve the understanding of thephysiological adaptation variations of Rhododendron species across elevation gradients in associationwith climate change in the mountains of southwestern China.

Deubiquitinating enzyme Josephin-2 stabilizes PHGDH to promote a cancer stem cell phenotype in hepatocellular carcinoma

Wang Ying,Li Ze-Xin,Wang Jian-Guo,Li Lu-Hao,Shen Wen-Long,Dang Xiao-Wei 한국유전학회 2023 Genes & Genomics Vol.45 No.2

Background Deubiquitinating enzymes (DUBs) have been shown to be possible targets for hepatocellular carcinoma (HCC) treatment. Objective This study was designed to reveal the effect and underlying mechanism of Josephin-2, a relatively newly defined DUB, in HCC progression. Methods SNU-387 and PLC/PRF/5 cells were used for in vitro functional assays. The levels of Josephin-2 and phosphoglycerate dehydrogenase (PHGDH) were determined using RT-qPCR and western blotting. Cell proliferation, migration and invasion were assessed by CCK-8, colony formation and Transwell. Spheroid-forming assay was performed to assess the cancer stem cell (CSC)-phenotype of HCC cells. A xenograft mice model was applied to verify the effect of Josephin-2 on HCC cell growth in vivo. Results Herein, we showed that Josephin-2 expression was negatively correlated with HCC patient survival in data from the online database. Cell experiments indicated that knockdown of Josephin-2 attenuated HCC cell malignant biological behaviors. Besides, Josephin-2 silencing also decreased the spheroid-formation while inhibited the expression of CSC biomarkers (CD133, OCT4, SOX2 and EpCAM) in HCC cells. Mechanistically, Josephin-2 had a deubiquitinating activity towards the regulation of PHGDH protein, the rate-limiting enzyme in the first step of serine biosynthesis pathway. Depletion of Josephin-2 enhanced the ubiquitination degradation of PHGDH and ultimately inhibited the proliferation and CSC-phenotype of HCC in vitro and in vivo. Conclusion Our work uncovered the regulatory effects of Josephin-2 on PHGDH protein stability and profiled its contribution in HCC malignant progression, which might provide a potential therapeutic target for HCC.

Identification of a Novel Human Zinc Finger Gene, ZNF438, with Transcription Inhibition Activity

( Zhao Min Zhong ),( Bo Wan ),( Yun Qiu ),( Jun Ni ),( Wen Wen Tang ),( Xin Ya Chen ),( Yun Yang ),( Su Qin Shen ),( Ying Wang ),( Mei Rong Bai ),( Qing Yu Lang ),( Long Yu ) 생화학분자생물학회 2007 BMB Reports Vol.40 No.4