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H Niitsu, T Hinoi, Y Kawaguchi, K Sentani, R Yuge, Y Kitadai, Y Sotomaru, T Adachi, Y Saito, M Miguchi, M Kochi, H Sada, M Shimomura, N Oue, W Yasui, H Ohdan
KRAS mutations occur in 30-40% of all cases of human colorectal cancer (CRC). However, to date, specific therapeutic agents against KRAS-mutated CRC have not been developed. We previously described the generation of mouse models of colon cancer with and without Kras mutations (CDX2P-G22Cre;Apc(flox/flox); LSL-Kras(G12D) and CDX2P-G22Cre;Apc(flox/flox) mice, respectively). Here, the two mouse models were compared to identify candidate genes, which may represent novel therapeutic targets or predictive biomarkers...
2016: Oncogenesis
Mohammad A Aleskandarany, Rezvan Abduljabbar, Ibraheem Ashankyty, Ahmed Elmouna, Dena Jerjees, Simak Ali, Laki Buluwela, Maria Diez-Rodriguez, Carlos Caldas, Andrew R Green, Ian O Ellis, Emad A Rakha
Differential prognostic roles of Androgen Receptor (AR) have been proposed in breast cancer (BC) depending on tumour oestrogen receptor (ER) status. This study aimed to evaluate the prognostic and/or predictive significance of AR expression in invasive BC. In this study AR expression was studied on a large (n = 1141) consecutive series of early-stage (I-III) BC using tissue microarray and immunohistochemistry (IHC). AR mRNA expression was assessed in a subset of cases. The prognostic impact of AR mRNA expression was externally validated using the online BC gene expression data sets (n = 25 data sets, 4078 patients)...
September 2016: Breast Cancer Research and Treatment
Jin-Kwan Lee, Janet Lee, Heounjeong Go, Chang Geun Lee, Suhyeon Kim, Hyun-Soo Kim, Hyeseong Cho, Kyeong Sook Choi, Geun-Hyoung Ha, Chang-Woo Lee
Five brain-expressed X-linked (BEX) gene members (BEX1-5) are arranged in tandem on chromosome X, and are highly conserved across diverse species. However, little is known about the function and role of BEX. This study represents a first attempt to demonstrate the molecular details of a novel oncogene BEX4. Among BEX proteins, BEX4 localizes to microtubules and spindle poles, and interacts with α-tubulin (α-TUB) and sirtuin 2 (SIRT2). The overexpression of BEX4 leads to the hyperacetylation of α-TUB by inhibiting SIRT2-mediated deacetylation...
2016: Cell Death & Disease
Phillip Zook, Harsh B Pathak, Martin Belinsky, Lawrence Gersz, Karthik Devarajan, Yan Zhou, Andrew K Godwin, Margaret von Mehren, Lori A Rink
PURPOSE: Gastrointestinal stromal tumors (GIST) generally harbor activating mutations in the receptor tyrosine kinase KIT or in the related platelet derived growth factor receptor alpha (PDGFRA). GIST treated with imatinib mesylate (IM) or second-line therapies that target mutant forms of these receptors generally escape disease control and progress over time. Inhibiting additional molecular targets may provide more substantial disease control. Recent studies have implicated the PI3-kinase/AKT pathway in the survival of IM-resistant GIST cell lines and tumors...
July 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Wei Gao, John Zeng-Hong Li, Si-Qi Chen, Chiao-Yun Chu, Jimmy Yu-Wai Chan, Thian-Sze Wong
BACKGROUND: Brain-expressed X-linked (BEX) 4 is a member of BEX family. The functional role of BEX4 in oral squamous cell carcinoma (OSCC) remains unknown. METHODS: Expression level of BEX family members (BEX1-5) in OSCC tissues and the paired normal epithelial were examined. Functions of epigenetic changes (DNA methylation and histone modifications) on BEX4 suppression in OSCC were examined by zebularine and trichostatin A (TSA) treatment on OSCC cell lines. Lentivector containing full-length BEX4 was used to generate OSCC cell lines with stable BEX4 expression...
2016: Journal of Experimental & Clinical Cancer Research: CR
Chunhui Jiang, Jing-Hua Wang, Feng Yue, Shihuan Kuang
Skeletal muscle development (myogenesis) is a complex but precisely orchestrated process involving spatiotemporal regulation of the proliferation, differentiation and fusion of myogenic progenitor cells (myoblasts). Here we identify brain expressed x-linked gene 1 (Bex1) as a transient, developmentally regulated gene involved in myoblast fusion. Bex1 expression is undetectable in adult muscles or in quiescent muscle stem cells (satellite cells). During embryonic myogenesis, however, Bex1 is robustly expressed by myogenin(+) differentiating myoblasts, but not by Pax7(+) proliferating myoblasts...
January 1, 2016: Developmental Biology
Hiroyuki Sagawa, Aya Naiki-Ito, Hiroyuki Kato, Taku Naiki, Yoriko Yamashita, Shugo Suzuki, Shinya Sato, Kosuke Shiomi, Akihisa Kato, Toshiya Kuno, Yoichi Matsuo, Masahiro Kimura, Hiromitsu Takeyama, Satoru Takahashi
Non-alcoholic steatohepatitis (NASH) has the potential to lead to the development of cirrhosis and hepatocellular carcinoma (HCC). Connexin (Cx) 32, a hepatocyte gap-junction protein, plays a preventive role in hepatocarcinogenesis. However, the precise contribution of Cx32 in the development of NASH has not been established. In this study, we aimed to clarify the role of Cx32 and the chemopreventive effect of luteolin, an antioxidant flavonoid, on the progression of NASH and NASH-related hepatocarcinogenesis...
December 2015: Carcinogenesis
Julhash U Kazi, Nuzhat N Kabir, Lars Rönnstrand
The Brain-Expressed X-linked (BEX) family proteins are comprised of five human proteins including BEX1, BEX2, BEX3, BEX4 and BEX5. BEX family proteins are expressed in a wide range of tissues and are known to play a role in neuronal development. Recent studies suggest a role of BEX family proteins in cancers. BEX1 expression is lost in a subgroup of patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Expression of BEX1 controls cell surface receptor signaling and restores imatinib response in resistant cells...
December 2015: Biochimica et Biophysica Acta
Oscar Lindblad, Tianfeng Li, Xianwei Su, Jianmin Sun, Nuzhat N Kabir, Fredrik Levander, Hui Zhao, Gang Lu, Lars Rönnstrand, Julhash U Kazi
Acute myeloid leukemia (AML) is a heterogeneous disease of the myeloid lineage. About 35% of AML patients carry an oncogenic FLT3 mutant making FLT3 an attractive target for treatment of AML. Major problems in the development of FLT3 inhibitors include lack of specificity, poor response and development of a resistant phenotype upon treatment. Further understanding of FLT3 signaling and discovery of novel regulators will therefore help to determine additional pharmacological targets in FLT3-driven AML. In this report, we identified BEX1 as a novel regulator of oncogenic FLT3-ITD-driven AML...
August 28, 2015: Oncotarget
Rezvan Abduljabbar, Ola H Negm, Chun-Fui Lai, Dena A Jerjees, Methaq Al-Kaabi, Mohamed R Hamed, Patrick J Tighe, Lakjaya Buluwela, Abhik Mukherjee, Andrew R Green, Simak Ali, Emad A Rakha, Ian O Ellis
The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily of transcription factors, which exerts anti-proliferative and anti-apoptotic activities. The GR is expressed in a large proportion of breast cancer (BC) although levels generally decrease during cancer progression. This study aimed to determine the clinical and biological significance of GR expression using a large series of early-stage BC with long-term follow-up and BC cell lines. Immunohistochemistry was used to assess the expression of GR in 999 cases of primary invasive BC prepared as tissue microarrays...
April 2015: Breast Cancer Research and Treatment
Eva M Fernandez, María D Díaz-Ceso, Marçal Vilar
Intrinsically disordered proteins (IDPs) are abundant in complex organisms. Due to their promiscuous nature and their ability to adopt several conformations IDPs constitute important points of network regulation. The family of Brain Expressed and X-linked (Bex) proteins consists of 5 members in humans (Bex1-5). Recent reports have implicated Bex proteins in transcriptional regulation and signaling pathways involved in neurodegeneration, cancer, cell cycle and tumor growth. However, structural and biophysical data for this protein family is almost non-existent...
2015: PloS One
Qian Xiao, Yeting Hu, Yue Liu, Zhanhuai Wang, Haitao Geng, Lifeng Hu, Dengyong Xu, Ke Wang, Lei Zheng, Shu Zheng, Kefeng Ding
An enhanced anti-apoptotic capacity of tumor cells plays an important role in the process of breakpoint cluster region/Abelson tyrosine kinase gene (BCR/ABL)-independent imatinib resistance. We have previously demonstrated that brain expressed X-linked 1 (BEX1) was silenced in secondary imatinib-resistant K562 cells and that re-expression of BEX1 can restore imatinib sensitivity resulting in the induction of apoptosis. However, the mechanism by which BEX1 executes its pro-apoptotic function remains unknown...
2014: PloS One
Maria Teresa De Angelis, Filomena Russo, Fulvio D'Angelo, Antonella Federico, Marica Gemei, Luigi Del Vecchio, Michele Ceccarelli, Mario De Felice, Geppino Falco
The generation of pancreatic endocrine and exocrine functional precursors from embryonic stem cells (ESCs) is an intriguing opportunity to address cell therapy challenges. The main goal of cellular regeneration is to derive, in vitro, pancreatic progenitor cells (PPCs) that retain the capacity to differentiate following the in vivo developmental ontogeny. In our work, we aim to refine the pancreatic in vitro cellular transitions, through the identification of the intrinsic factors that mark the pancreas budding process at embryonic stage 10...
April 2014: Stem Cell Reviews
Hirokazu Tanaka, Tomasz Nodzyłski, Saeko Kitakura, Mugurel I Feraru, Michiko Sasabe, Tomomi Ishikawa, Jürgen Kleine-Vehn, Tatsuo Kakimoto, Jiři Friml
Correct positioning of membrane proteins is an essential process in eukaryotic organisms. The plant hormone auxin is distributed through intercellular transport and triggers various cellular responses. Auxin transporters of the PIN-FORMED (PIN) family localize asymmetrically at the plasma membrane (PM) and mediate the directional transport of auxin between cells. A fungal toxin, brefeldin A (BFA), inhibits a subset of guanine nucleotide exchange factors for ADP-ribosylation factor small GTPases (ARF GEFs) including GNOM, which plays a major role in localization of PIN1 predominantly to the basal side of the PM...
April 2014: Plant & Cell Physiology
Katherine Karakoula, Thomas S Jacques, Kim P Phipps, William Harkness, Dominic Thompson, Brian N Harding, John L Darling, Tracy J Warr
Promoter hypermethylation and transcriptional silencing is a common epigenetic mechanism of gene inactivation in cancer. To identify targets of epigenetic silencing in paediatric intracranial ependymoma, we used a pharmacological unmasking approach through treatment of 3 ependymoma short-term cell cultures with the demethylating agent 5-Aza-2'-deoxycytidine followed by global expression microarray analysis. We identified 55 candidate epigenetically silenced genes, which are involved in the regulation of apoptosis, Wnt signalling, p53 and cell differentiation...
April 28, 2014: Cancer Letters
Jia-Hao Jiang, Qiang Gao, Xi-Zhong Shen, Yao Yu, Fang-Ming Gu, Jun Yan, Jin-Feng Pan, Fei Jin, Jia Fan, Jian Zhou, Xiao-Wu Huang
BACKGROUND AND OBJECTIVE: Genetic epidemiological data in hepatocellular carcinoma (HCC) pedigrees indicate a pattern of X-linked recessive inheritance of HCC susceptibility genes. This study is designed to test the hypothesis that there are genes conferring susceptibility to HCC located on the X-chromosome. METHODS: An X-chromosomal association study was conducted among Chinese men recruited from an area with a high prevalence of HCC. The candidate gene was further investigated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR)...
December 2013: Clinics and Research in Hepatology and Gastroenterology
Wendy M White, Brian Brost, Zhifu Sun, Carl Rose, Iasmina Craici, Steven J Wagner, Stephen T Turner, Vesna D Garovic
OBJECTIVE: To compare genome-wide methylation profiles in maternal leukocyte DNA between normotensive and preeclamptic pregnant women at delivery. METHODS: Age, body mass index matched case-control comparison of methylation at 27,578 cytosine-- guanine sites in 14,495 genes in maternal leukocyte DNA in women with preeclampsia (PE; n = 14) and normotensive controls (n = 14). RESULTS: PE was associated with widespread differential methylation favoring hypermethylation...
August 2013: Hypertension in Pregnancy
Chia-Huei Lee, Thian-Sze Wong, Jimmy Yu-Wai Chan, Shao-Chun Lu, Pinpin Lin, Ann-Joy Cheng, Yin-Ju Chen, Jeffrey Shu-Ming Chang, Shu-Huei Hsiao, Yu-Wei Leu, Chuan-I Li, Jenn-Ren Hsiao, Jang-Yang Chang
The strong associations between oral squamous cell carcinoma (OSCC) and dietary habits such as alcohol consumption (A), betel quid chewing (B) and cigarette smoking (C) and its predominance in men have been well documented; however, systemic analysis of OSCC is limited. Our study applied high-throughput screening methods to identify causative epigenetic targets in a cohort of men with ABC-associated OSCC. We identified BEX1 and LDOC1 as two epigenetically silenced X-linked tumour suppressors and demonstrated a functional link between the transcription of BEX1 and LDOC1 and promoter hypermethylation...
July 2013: Journal of Pathology
Takeki Uehara, Garrett R Ainslie, Kristi Kutanzi, Igor P Pogribny, Levan Muskhelishvili, Takeshi Izawa, Jyoji Yamate, Oksana Kosyk, Svitlana Shymonyak, Blair U Bradford, Gary A Boorman, Ramon Bataller, Ivan Rusyn
Hepatocellular carcinoma (HCC) mostly develops in patients with advanced fibrosis; however, the mechanisms of interaction between a genotoxic insult and fibrogenesis are not well understood. This study tested a hypothesis that fibrosis promotes HCC via a mechanism that involves activation of liver stem cells. First, B6C3F1 mice were administered diethylnitrosamine (DEN; single ip injection of 1mg/kg at 14 days of age). Second, carbon tetrachloride (CCl(4); 0.2ml/kg, 2/week ip starting at 8 weeks of age) was administered for 9 or 14 weeks to develop advanced liver fibrosis...
March 2013: Toxicological Sciences: An Official Journal of the Society of Toxicology
Chi-Hun Park, Young Hee Jeong, Yeun-Ik Jeong, Se-Yeong Lee, Yeon-Woo Jeong, Taeyoung Shin, Nam-Hyung Kim, Eui-Bae Jeung, Sang-Hwan Hyun, Chang-Kyu Lee, Eunsong Lee, Woo Suk Hwang
To determine the presence of sexual dimorphic transcription and how in vitro culture environments influence X-linked gene transcription patterns in preimplantation embryos, we analyzed mRNA expression levels in in vivo-derived, in vitro-fertilized (IVF), and cloned porcine blastocysts. Our results clearly show that sex-biased expression occurred between female and male in vivo blastocysts in X-linked genes. The expression levels of XIST, G6PD, HPRT1, PGK1, and BEX1 were significantly higher in female than in male blastocysts, but ZXDA displayed higher levels in male than in female blastocysts...
2012: PloS One
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