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Chiara V Ragni, Nicolas Diguet, Jean-François Le Garrec, Marta Novotova, Tatiana P Resende, Sorin Pop, Nicolas Charon, Laurent Guillemot, Lisa Kitasato, Caroline Badouel, Alexandre Dufour, Jean-Christophe Olivo-Marin, Alain Trouvé, Helen McNeill, Sigolène M Meilhac
Although in flies the atypical cadherin Fat is an upstream regulator of Hippo signalling, the closest mammalian homologue, Fat4, has been shown to regulate tissue polarity rather than growth. Here we show in the mouse heart that Fat4 modulates Hippo signalling to restrict growth. Fat4 mutant myocardium is thicker, with increased cardiomyocyte size and proliferation, and this is mediated by an upregulation of the transcriptional activity of Yap1, an effector of the Hippo pathway. Fat4 is not required for the canonical activation of Hippo kinases but it sequesters a partner of Yap1, Amotl1, out of the nucleus...
February 27, 2017: Nature Communications
Sadegh Fattahi, Maryam Pilehchian Langroudi, Ali Akbar Samadani, Novin Nikbakhsh, Mohsen Asouri, Haleh Akhavan-Niaki
Accurate expression profiling is imperative for understanding the biological roles of mRNAs. Real-time PCR have been at the forefront of biological innovation in detection and monitoring of gene expression, however, fluorophore-labeled oligonucleotides and double-stranded DNA binding dyes, the two most frequently used dyes in RNA detection, are not very cost effective and have poor specificity, respectively. We have developed a cost effective and specific approach for mRNA expression profiling via added unique sequence index (USI) to cDNAs before amplification...
March 2017: Journal of Cell Communication and Signaling
Xiaofeng Zhang, Jinghua Liu, Xiao Liang, Jiang Chen, Junjie Hong, Libo Li, Qiang He, Xiujun Cai
Intercellular adhesions are vital hubs for signaling pathways during multicellular development and animal morphogenesis. In eukaryotes, under aberrant intracellular conditions, cadherins are abnormally regulated, which can result in cellular pathologies such as carcinoma, kidney disease, and autoimmune diseases. As a member of the Ca(2+)-dependent adhesion super-family, Fat proteins were first described in the 1920s as an inheritable lethal mutant phenotype in Drosophila, consisting of four member proteins, FAT1, FAT2, FAT3, and FAT4, all of which are highly conserved in structure...
2016: OncoTargets and Therapy
Lingmi Hou, Maoshan Chen, Xiaobo Zhao, Jingdong Li, Shishan Deng, Jiani Hu, Hongwei Yang, Jun Jiang
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is often associated with biologic behavior with frequent distant metastasis. FAT tumor suppressor homolog 4 (FAT4), a cadherin-related protein, is involved in a variety of biological processes as a tumor suppressor; however, the role of FAT4 in TNBC is still unclear. The aim of our study was to identify the role of FAT4 in TNBC and examine the underlying molecular mechanisms. The expression of FAT4 was evaluated by immunohistochemistry, western blotting, and qRT-PCR in a series of TNBC tissues...
November 28, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Zheng Ping, Gene P Siegal, Shuko Harada, Isam-Eldin Eltoum, Mariam Youssef, Tiansheng Shen, Jianbo He, Yingjie Huang, Dongquan Chen, Yiping Li, Kirby I Bland, Helena R Chang, Dejun Shen
E-cadherin (CDH1) is a glycoprotein that mediates adhesion between epithelial cells and also suppresses cancer invasion. Mutation or deletion of the CDH1 gene has been reported in 30-60% cases of invasive lobular carcinoma (ILC). However, little is known about genomic differences between ILC with and without a CDH1 alteration. Therefore, we analyzed whole genome sequencing data of 169 ILC cases from The Cancer Genome Atlas (TCGA) to address this deficiency. Our study shows that CDH1 gene was altered in 59.2% (100/169) of ILC...
December 6, 2016: Oncotarget
Maryam Pilehchian Langroudi, Novin Nikbakhsh, Ali Akbar Samadani, Sadegh Fattahi, Hassan Taheri, Shahryar Shafaei, Galia Amirbozorgi, Reza Pilehchian Langroudi, Haleh Akhavan-Niaki
Gastric cancer is one of the major causes of death due to cancer in the world. It is a multi-factorial disease with epigenetic factors being also involved in its development. FAT4 is a tumor suppressor gene exerting an important role in cell adhesion. This study aimed at analyzing FAT4 expression and promoter methylation in gastric cancer. FAT4 expression was studied in 30 tumoral tissues and their non-tumoral counterparts using Taqman real time PCR method. Promoter methylation was assessed using bisulfite conversion method followed by sequencing...
March 2017: Journal of Cell Communication and Signaling
Anna Kuta, Yaopan Mao, Tina Martin, Catia Ferreira de Sousa, Danielle Whiting, Sana Zakaria, Ivan Crespo-Enriquez, Philippa Evans, Bartosz Balczerski, Baljinder Mankoo, Kenneth D Irvine, Philippa H Francis-West
The protocadherins Fat4 and Dchs1 act as a receptor-ligand pair to regulate many developmental processes in mice and humans, including development of the vertebrae. Based on conservation of function between Drosophila and mammals, Fat4-Dchs1 signalling has been proposed to regulate planar cell polarity (PCP) and activity of the Hippo effectors Yap and Taz, which regulate cell proliferation, survival and differentiation. There is strong evidence for Fat regulation of PCP in mammals but the link with the Hippo pathway is unclear...
July 1, 2016: Development
Yaopan Mao, Anna Kuta, Ivan Crespo-Enriquez, Danielle Whiting, Tina Martin, Joanna Mulvaney, Kenneth D Irvine, Philippa Francis-West
Skeletal shape varies widely across species as adaptation to specialized modes of feeding and locomotion, but how skeletal shape is established is unknown. An example of extreme diversity in the shape of a skeletal structure can be seen in the sternum, which varies considerably across species. Here we show that the Dchs1-Fat4 planar cell polarity pathway controls cell orientation in the early skeletal condensation to define the shape and relative dimensions of the mouse sternum. These changes fit a model of cell intercalation along differential Dchs1-Fat4 activity that drives a simultaneous narrowing, thickening and elongation of the sternum...
May 5, 2016: Nature Communications
Peng He, Lin Sun, Dan Zhu, Hong Zhang, Liang Zhang, Yujie Guo, Siwen Liu, Jingjing Zhou, Xiaoyan Xu, Peng Xie
Endogenous bornavirus-like nucleoprotein elements (EBLNs) have been discovered in the genomes of various animals including humans, whose functions have been seldom studied. To explore the biological functions of human EBLNs, we constructed a lentiviral vector expressing a short-hairpin RNA against human EBLN1, which successfully inhibited EBLN1 expression by above 80% in infected human oligodendroglia cells (OL cells). We found that EBLN1 silencing suppressed cell proliferation, induced G2/M phase arrest, and promoted apoptosis in OL cells...
March 24, 2016: International Journal of Molecular Sciences
Satoshi Yoshida, Satoshi Yamashita, Tohru Niwa, Akiko Mori, Seiji Ito, Masao Ichinose, Toshikazu Ushijima
BACKGROUND: Gastric cancer (GC) is highly influenced by aberrant methylation, and accumulation of aberrant methylation in gastric mucosae produces an epigenetic field for cancerization. Nevertheless, the individual driver genes involved in such field cancerization are still unclear. Here, we aimed to demonstrate that FAT4, a novel tumor suppressor identified by exome sequencing of GC, is methylation-silenced and that such methylation is involved in epigenetic field cancerization for GC...
January 2017: Gastric Cancer
Akito Dobashi, Naoko Tsuyama, Reimi Asaka, Yuki Togashi, Kyoko Ueda, Seiji Sakata, Satoko Baba, Kana Sakamoto, Kiyohiko Hatake, Kengo Takeuchi
Extranodal natural killer/T cell lymphoma (ENKTL) is a rare subtype of lymphoma. Recurrent mutations in the JAK-STAT pathway, recently reported in ENKTL cases, are interesting in terms of both pathogenesis and inhibitor therapy. However, the frequencies of these mutations are low and variable among reports, and other pathognomonic mutations in ENKTL remain to be elucidated. In the present study, targeted capture sequencing of 602 cancer-related genes from 25 frozen ENKTL samples was performed, 11 of which were matched to normal samples...
May 2016: Genes, Chromosomes & Cancer
Jie-Yi Shi, Qingfeng Xing, Meng Duan, Zhi-Chao Wang, Liu-Xiao Yang, Ying-Jun Zhao, Xiao-Ying Wang, Yun Liu, Minghua Deng, Zhen-Bin Ding, Ai-Wu Ke, Jian Zhou, Jia Fan, Ya Cao, Jiping Wang, Ruibin Xi, Qiang Gao
Multifocal tumors developed either as independent tumors or as intrahepatic metastases, are very common in primary liver cancer. However, their molecular pathogenesis remains elusive. Herein, a patient with synchronous two hepatocellular carcinoma (HCC, designated as HCC-A and HCC-B) and one intrahepatic cholangiocarcinoma (ICC), as well as two postoperative recurrent tumors, was enrolled. Multiregional whole-exome sequencing was applied to these tumors to delineate the clonality and heterogeneity. The three primary tumors showed almost no overlaps in mutations and copy number variations...
January 19, 2016: Oncotarget
C C Mason, J S Khorashad, S K Tantravahi, T W Kelley, M S Zabriskie, D Yan, A D Pomicter, K R Reynolds, A M Eiring, Z Kronenberg, R L Sherman, J W Tyner, B K Dalley, K-H Dao, M Yandell, B J Druker, J Gotlib, T O'Hare, M W Deininger
Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related...
April 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Jian Cai, Dan Feng, Liang Hu, Haiyang Chen, Guangzhen Yang, Qingping Cai, Chunfang Gao, Dong Wei
BACKGROUND: FAT4, a cadherin-related protein, was shown to function as a tumour suppressor; however, its role in human gastric cancer remains largely unknown. Here, we investigated the role of FAT4 in gastric cancer and examined the underlying molecular mechanisms. METHODS: The expression of FAT4 was evaluated by immunohistochemistry, western blotting, and qRT-PCR in relation to the clinicopathological characteristics of gastric cancer patients. The effects of FAT4 silencing on cell proliferation, migration, and invasion were assessed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) assay, and migration and invasion assays in gastric cancer cell lines in vitro and in a mouse xenograft model in vivo...
December 22, 2015: British Journal of Cancer
Liangang Ma, Jianxin Cui, Hongqing Xi, Shibo Bian, Bo Wei, Lin Chen
Fat4 functions as a Hippo signaling regulator which is involved in mammalian tissue development, differentiation and tumorigenesis. Loss of Fat4 due to frequent gene mutation was detected in a variety of tumors including gastric cancer, where Fat4 was recognized as a tumor suppressor, repressing cancer cell proliferation and adhesion. However, the detailed mechanisms linking Fat4 to its diverse functions and clinicopathological characteristics in gastric cancer remain unclear. Here, we silenced Fat4 using Fat4-shRNA in gastric cancer cells and found that this suppression led to the increase in phosphorylated Yap and nuclear accumulation of Yap, which associated to the promoted proliferation, migration and cell cycle progression...
2016: Cancer Biology & Therapy
Tomoko Ohmori, Shunsuke Tanigawa, Yusuke Kaku, Sayoko Fujimura, Ryuichi Nishinakamura
The mammalian kidney develops from reciprocal interactions between the metanephric mesenchyme and ureteric bud, the former of which contains nephron progenitors. The third lineage, the stroma, fills up the interstitial space and is derived from distinct progenitors that express the transcription factor Foxd1. We showed previously that deletion of the nuclear factor Sall1 in nephron progenitors leads to their depletion in mice. However, Sall1 is expressed not only in nephron progenitors but also in stromal progenitors...
2015: Scientific Reports
Manoj Garg, Yasunobu Nagata, Deepika Kanojia, Anand Mayakonda, Kenichi Yoshida, Sreya Haridas Keloth, Zhi Jiang Zang, Yusuke Okuno, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Ling-Wen Ding, Tamara Alpermann, Qiao-Yang Sun, De-Chen Lin, Wenwen Chien, Vikas Madan, Li-Zhen Liu, Kar-Tong Tan, Abhishek Sampath, Subhashree Venkatesan, Koiti Inokuchi, Satoshi Wakita, Hiroki Yamaguchi, Wee Joo Chng, Shirley-Kow Yin Kham, Allen Eng-Juh Yeoh, Masashi Sanada, Joanna Schiller, Karl-Anton Kreuzer, Steven M Kornblau, Hagop M Kantarjian, Torsten Haferlach, Michael Lill, Ming-Chung Kuo, Lee-Yung Shih, Igor-Wolfgang Blau, Olga Blau, Henry Yang, Seishi Ogawa, H Phillip Koeffler
Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy with a grave prognosis. To identify the mutational spectrum associated with relapse, whole-exome sequencing was performed on 13 matched diagnosis, relapse, and remission trios followed by targeted sequencing of 299 genes in 67 FLT3-ITD patients. The FLT3-ITD genome has an average of 13 mutations per sample, similar to other AML subtypes, which is a low mutation rate compared with that in solid tumors...
November 26, 2015: Blood
A Sebio, S Matsusaka, W Zhang, D Yang, Y Ning, S Stremitzer, S Stintzing, Y Sunakawa, S Yamauchi, Y Fujimoto, M Ueno, H-J Lenz
The Hippo pathway regulates tissue growth and cell fate. In colon cancer, Hippo pathway deregulation promotes cellular quiescence and resistance to 5-Fluorouracil (5-Fu). In this study, 14 polymorphisms in 8 genes involved in the Hippo pathway (MST1, MST2, LATS1, LATS2, YAP, TAZ, FAT4 and RASSF1A) were evaluated as recurrence predictors in 194 patients with stages II/III colon cancer treated with 5-Fu-based adjuvant chemotherapy. Patients with a RASSF1A rs2236947 AA genotype had higher 3-year recurrence rate than patients with CA/CC genotypes (56 vs 33%, hazard ratio (HR): 1...
2016: Pharmacogenomics Journal
Y Lin, Z Wu, W Guo, J Li
Gastric cancer (GC) is one of the most common malignancies worldwide. Although some driver genes have been identified in GC, the molecular compositions of GC have not been fully understood. The development of next-generation sequencing (NGS) provides a high-throughput and systematic method to identify all genetic alterations in the cancer genome, especially in the field of mutation detection. NGS studies in GC have discovered some novel driver mutations. In this review, we focused on novel gene mutations discovered by NGS studies, along with some well-known driver genes in GC...
September 2015: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Feixiong Cheng, Chuang Liu, Chen-Ching Lin, Junfei Zhao, Peilin Jia, Wen-Hsiung Li, Zhongming Zhao
Cancer development and progression result from somatic evolution by an accumulation of genomic alterations. The effects of those alterations on the fitness of somatic cells lead to evolutionary adaptations such as increased cell proliferation, angiogenesis, and altered anticancer drug responses. However, there are few general mathematical models to quantitatively examine how perturbations of a single gene shape subsequent evolution of the cancer genome. In this study, we proposed the gene gravity model to study the evolution of cancer genomes by incorporating the genome-wide transcription and somatic mutation profiles of ~3,000 tumors across 9 cancer types from The Cancer Genome Atlas into a broad gene network...
September 2015: PLoS Computational Biology
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