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Yunhe Gao, Aizhen Cai, Hongqing Xi, Jiyang Li, Wei Xu, Yanmei Zhang, Kecheng Zhang, Jianxin Cui, Xiaosong Wu, Bo Wei, Lin Chen
BACKGROUND: Ring finger protein 43 (RNF43) is a member of the transmembrane E3 ubiquitin ligase family that was originally found in stem cells and plays important roles in tumor formation and progression. Our previous study indicated that RNF43 might be a tumor suppressor protein in gastric cancer. Given its antagonistic relationship with leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5), one of the gastric cancer stem cell markers, investigation of the potential role of RNF43 in gastric stem cancer cells is necessary...
April 26, 2017: Stem Cell Research & Therapy
Francisco Sánchez-Vega, Valer Gotea, Yun-Ching Chen, Laura Elnitski
Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational research, great emphasis has been placed on the analysis and molecular characterization of the CpG island methylator phenotype (CIMP), defined as widespread hypermethylation of CpG islands in clinically distinct subsets of cancer patients. Here, we present an overview of previous work in this field and also explore some open questions using cross-platform data for esophageal, gastric, and colorectal adenocarcinomas from The Cancer Genome Atlas...
March 15, 2017: World Journal of Gastrointestinal Oncology
Hiroya Taniguchi, Satoru Iwasa, Kentaro Yamazaki, Takayuki Yoshino, Chika Kiryu, Yoshiharu Naka, Ei Leen Liew, Yuh Sakata
OCV-C02 is a peptide vaccine consisting of two peptide epitopes derived from ring finger protein 43 (RNF43) and translocase of outer mitochondrial membrane 34 (TOMM34). This Phase 1 study assessed the safety, preliminary efficacy and immunological responses following OCV-C02 administration in patients with advanced or relapsed colorectal cancer who were intolerant or refractory to standard chemotherapy. The primary endpoint was any occurrence of dose limiting toxicity (DLT) during Cycle 1. The secondary endpoints were treatment-emergent adverse events, efficacy and immunological responses...
March 7, 2017: Cancer Science
Waki Hosoda, Peter Chianchiano, James F Griffin, Meredith E Pittman, Lodewijk Aa Brosens, Michaël Noë, Jun Yu, Koji Shindo, Masaya Suenaga, Neda Rezaee, Raluca Yonescu, Yi Ning, Jorge Albores-Saavedra, Naohiko Yoshizawa, Kenichi Harada, Akihiko Yoshizawa, Keiji Hanada, Shuji Yonehara, Michio Shimizu, Takeshi Uehara, Jaswinder S Samra, Anthony J Gill, Christopher L Wolfgang, Michael G Goggins, Ralph H Hruban, Laura D Wood
High-grade pancreatic intraepithelial neoplasia (HG-PanIN) is the major precursor of pancreatic ductal adenocarcinoma (PDAC) and is an ideal target for early detection. To characterize pure HG-PanIN, we analysed 23 isolated HG-PanIN lesions occurring in the absence of PDAC. Whole-exome sequencing of five of these HG-PanIN lesions revealed a median of 33 somatic mutations per lesion, with a total of 318 mutated genes. Targeted next-generation sequencing of 17 HG-PanIN lesions identified KRAS mutations in 94% of the lesions...
February 11, 2017: Journal of Pathology
Georgios D Lianos, Georgios K Glantzounis, Christina D Bali, Christos Katsios, Dimitrios H Roukos
AIM: By identifying cancer driver genes involved in tumorigenesis, whole-exome sequencing (WES) analyses enable the development of robust biomarkers and novel therapeutic targets to reach precision oncology. PATIENTS & METHODS: WES analyses were performed in matched gastric cancer-normal gastric tissues from two patients. We compared genes highlighted with those of a database and recent WES/whole-genome sequencing studies. RESULTS: We identified 32 highlighted gastric cancer genes, two of these (DEFB118 and RNF43) may provide future potential clinical implications...
April 2017: Future Oncology
Zachary Steinhart, Zvezdan Pavlovic, Megha Chandrashekhar, Traver Hart, Xiaowei Wang, Xiaoyu Zhang, Mélanie Robitaille, Kevin R Brown, Sridevi Jaksani, René Overmeer, Sylvia F Boj, Jarrett Adams, James Pan, Hans Clevers, Sachdev Sidhu, Jason Moffat, Stéphane Angers
Forward genetic screens with CRISPR-Cas9 genome editing enable high-resolution detection of genetic vulnerabilities in cancer cells. We conducted genome-wide CRISPR-Cas9 screens in RNF43-mutant pancreatic ductal adenocarcinoma (PDAC) cells, which rely on Wnt signaling for proliferation. Through these screens, we discovered a unique requirement for a Wnt signaling circuit: engaging FZD5, one of the ten Frizzled receptors encoded in the human genome. Our results uncover an underappreciated level of context-dependent specificity at the Wnt receptor level...
January 2017: Nature Medicine
Jia-Huei Tsai, Jau-Yu Liau, Chang-Tsu Yuan, Mei-Ling Cheng, Ray-Hwang Yuan, Yung-Ming Jeng
AIMS: RNF43 is a tumour suppressor gene that suppresses the Wnt-β-catenin signalling pathway. We investigated the role of RNF43 in intraductal papillary neoplasm of the bile duct (IPNB). METHODS AND RESULTS: We conducted mutation analysis of RNF43 in 50 IPNBs, and identified six (12%) RNF43 mutations. RNF43 mutation was more frequent in the intestinal subtype of IPNB (17%) than in the gastric/pancreatobiliary subtype (5%). There was a strong association of RNF43 mutation with GNAS (P = 0...
April 2017: Histopathology
Lara Planas-Paz, Vanessa Orsini, Luke Boulter, Diego Calabrese, Monika Pikiolek, Florian Nigsch, Yang Xie, Guglielmo Roma, Adriana Donovan, Patricia Marti, Nicolau Beckmann, Michael T Dill, Walter Carbone, Sebastian Bergling, Andrea Isken, Matthias Mueller, Bernd Kinzel, Yi Yang, Xiaohong Mao, Thomas B Nicholson, Raffaella Zamponi, Paola Capodieci, Reginald Valdez, Daniel Rivera, Andreas Loew, Chinweike Ukomadu, Luigi M Terracciano, Tewis Bouwmeester, Feng Cong, Markus H Heim, Stuart J Forbes, Heinz Ruffner, Jan S Tchorz
No abstract text is available yet for this article.
October 27, 2016: Nature Cell Biology
Catherine E Bond, Diane M McKeone, Murugan Kalimutho, Mark L Bettington, Sally-Ann Pearson, Troy D Dumenil, Leesa F Wockner, Matthew Burge, Barbara A Leggett, Vicki L J Whitehall
Serrated pathway colorectal cancers (CRCs) are characterised by a BRAF mutation and half display microsatellite instability (MSI). The Wnt pathway is commonly upregulated in conventional CRC through APC mutation. By contrast, serrated cancers do not mutate APC. We investigated mutation of the ubiquitin ligases RNF43 and ZNRF3 as alternate mechanism of altering the Wnt signal in serrated colorectal neoplasia. RNF43 was mutated in 47/54(87%) BRAF mutant/MSI and 8/33(24%) BRAF mutant/microsatellite stable cancers compared to only 3/79(4%) BRAF wildtype cancers (p<0...
October 25, 2016: Oncotarget
Anette Heller, Assia L Angelova, Sonja Bauer, Svitlana P Grekova, Marc Aprahamian, Jean Rommelaere, Michael Volkmar, Johannes W G Janssen, Nathalie Bauer, Ingrid Herr, Thomas Giese, Matthias M Gaida, Frank Bergmann, Thilo Hackert, Stefan Fritz, Nathalia A Giese
OBJECTIVES: Our aim was to establish and characterize a novel pancreatic ductal adenocarcinoma cell line from a patient in whom the origin of the invasive carcinoma could be traced back to the intraductal papillary mucinous neoplasm (IPMN) precursor lesion. METHODS: The primary patient-derived tumor was propagated in immunocompromised mice for 2 generations and used to establish a continuous in vitro culture termed ASAN-PaCa. Transplantation to fertilized chicken eggs confirmed the tumorigenic potential in vivo...
November 2016: Pancreas
Byung-Hoon Min, Jinha Hwang, Nayoung K D Kim, Gibeom Park, So Young Kang, Sangjeong Ahn, Soomin Ahn, Sang Yun Ha, Yun Kyung Lee, Ryoji Kushima, Michael Van Vrancken, Min Jung Kim, Changho Park, Ha Young Park, Jeesoo Chae, Se Song Jang, Sung Jin Kim, Young-Ho Kim, Jong-Il Kim, Kyoung-Mee Kim
Several recurrent mutations and epigenetic changes have been identified in advanced gastric cancer, yet genetic alterations associated with early gastric carcinogenesis and malignant transformation remain unclear. We investigated genomic and transcriptomic landscape of adenomas with low-grade dysplasia (LGD) and high-grade dysplasia (HGD) and intestinal-type early gastric cancer (EGC). Results were validated in an independent cohort that included EGCs directly adjacent to adenoma (EGC-adenoma) which were in the process of malignant transformation and de novo EGCs which do not seem to have been derived from adenoma...
August 11, 2016: Journal of Pathology
Ju-Han Lee, Younghye Kim, Jung-Woo Choi, Young-Sik Kim
BACKGROUND: The prevalence and clinical significances of KRAS, GNAS, and RNF43 mutations in patients with pancreatic intraductal papillary mucinous neoplasm (IPMN) remain elusive. To evaluate the incidence of the gene mutations and clinicopathologic differences between KRAS and GNAS mutations in pancreatic cystic lesions, we performed a meta-analysis of published 33 KRAS, 11 GNAS, and 4 RNF43 studies including 1253, 835, and 143 cases, respectively. METHODS: We pooled the results of relevant studies identified using the PubMed and EMBASE databases...
2016: SpringerPlus
Huai-Xiang Hao, Xiaomo Jiang, Feng Cong
Aberrant activation of the Wnt/β-catenin pathway is frequently found in various cancers, often through mutations of downstream components. Inhibiting β-catenin signaling in tumors with downstream pathway mutations remains challenging, due to a lack of favorable targets. On the other hand, targeting upstream components of the Wnt pathway is rather straightforward. However, it is difficult to identify tumors addicted to autocrine or paracrine Wnt signaling. Discovery of the R-spondin-ZNRF3/RNF43 signaling module and its genetic alterations in cancers represents a breakthrough in this area...
June 8, 2016: Cancers
Helen H N Yan, Jeffrey C W Lai, Siu Lun Ho, Wai Keung Leung, Wai Lun Law, Janet F Y Lee, Anthony K W Chan, Wai Yin Tsui, Annie S Y Chan, Bernard C H Lee, Sarah S K Yue, Alice H Y Man, Hans Clevers, Siu Tsan Yuen, Suet Yi Leung
OBJECTIVE: Serrated polyps (hyperplastic polyps, sessile or traditional serrated adenomas), which can arise in a sporadic or polyposis setting, predispose to colorectal cancer (CRC), especially those with microsatellite instability (MSI) due to MLH1 promoter methylation (MLH1(me+)). We investigate genetic alterations in the serrated polyposis pathway. DESIGN: We used a combination of exome sequencing and target gene Sanger sequencing to study serrated polyposis families, sporadic serrated polyps and CRCs, with validation by analysis of The Cancer Genome Atlas (TCGA) cohort, followed by organoid-based functional studies...
June 21, 2016: Gut
Jia-Huei Tsai, Jau-Yu Liau, Chang-Tsu Yuan, Yu-Lin Lin, Li-Hui Tseng, Mei-Ling Cheng, Yung-Ming Jeng
RNF43 is an E3 ligase that suppresses the Wnt/β-catenin signaling pathway and is frequently mutated in microsatellite-unstable colorectal carcinoma. To investigate the pathogenetic role of RNF43 in the serrated pathway, we conducted mutation analysis of RNF43 in several types of colorectal neoplasms. RNF43 mutation was found in 2 of 20 (10%) sessile serrated adenomas, 10 of 36 (28%) traditional serrated adenomas, 7 of 37 (19%) traditional serrated adenomas with cytologic dysplasia, and 9 of 31 (29%) BRAF-mutated/microsatellite-stable colorectal carcinomas; however, no mutation was found in 30 tubulovillous/villous adenomas...
October 2016: American Journal of Surgical Pathology
Gui-Xun Shi, Wei-Wei Mao, Xin-Feng Zheng, Lei-Sheng Jiang
R-spondins are a family of four secreted proteins and act as agonists of the canonical Wnt/β-catenin signaling pathway. They are broadly expressed in different phases of skeleton tissues. Recently, three closely related leucine-rich repeat containing G-protein-coupled receptors (Lgr4/5/6) have been identified as the new and exact receptors of R-spondins. On the cell surface, R-spondins binding with Lgr4/5/6 and Znrf3/Rnf43 lead to reduced turnover of Wnts-receptors and potentiate Wnt/β-catenin signaling pathway which is critical for the control of bone development and remodeling...
November 2016: Progress in Biophysics and Molecular Biology
Babita Madan, Matthew P Walker, Robert Young, Laura Quick, Kelly A Orgel, Meagan Ryan, Priti Gupta, Ian C Henrich, Marc Ferrer, Shane Marine, Brian S Roberts, William T Arthur, Jason D Berndt, Andre M Oliveira, Randall T Moon, David M Virshup, Margaret M Chou, Michael B Major
The Wnt signaling pathways play pivotal roles in carcinogenesis. Modulation of the cell-surface abundance of Wnt receptors is emerging as an important mechanism for regulating sensitivity to Wnt ligands. Endocytosis and degradation of the Wnt receptors Frizzled (Fzd) and lipoprotein-related protein 6 (LRP6) are regulated by the E3 ubiquitin ligases zinc and ring finger 3 (ZNRF3) and ring finger protein 43 (RNF43), which are disrupted in cancer. In a genome-wide small interfering RNA screen, we identified the deubiquitylase ubiquitin-specific protease 6 (USP6) as a potent activator of Wnt signaling...
May 24, 2016: Proceedings of the National Academy of Sciences of the United States of America
Walter Birchmeier
Wnt/β-catenin signalling is an important regulator of liver development, zonation and regeneration. The cell surface complex RSPO-LGR4/5-ZNF3/RNF43 is now shown to direct Wnt/β-catenin signalling in orchestrating the division of the liver into functionally distinct metabolic zones, providing insights into the mechanisms that influence organ development and regeneration.
April 27, 2016: Nature Cell Biology
Lara Planas-Paz, Vanessa Orsini, Luke Boulter, Diego Calabrese, Monika Pikiolek, Florian Nigsch, Yang Xie, Guglielmo Roma, Adriana Donovan, Patricia Marti, Nicolau Beckmann, Michael T Dill, Walter Carbone, Sebastian Bergling, Andrea Isken, Matthias Mueller, Bernd Kinzel, Yi Yang, Xiaohong Mao, Thomas B Nicholson, Raffaella Zamponi, Paola Capodieci, Reginald Valdez, Daniel Rivera, Andreas Loew, Chinweike Ukomadu, Luigi M Terracciano, Tewis Bouwmeester, Feng Cong, Markus H Heim, Stuart J Forbes, Heinz Ruffner, Jan S Tchorz
LGR4/5 receptors and their cognate RSPO ligands potentiate Wnt/β-catenin signalling and promote proliferation and tissue homeostasis in epithelial stem cell compartments. In the liver, metabolic zonation requires a Wnt/β-catenin signalling gradient, but the instructive mechanism controlling its spatiotemporal regulation is not known. We have now identified the RSPO-LGR4/5-ZNRF3/RNF43 module as a master regulator of Wnt/β-catenin-mediated metabolic liver zonation. Liver-specific LGR4/5 loss of function (LOF) or RSPO blockade disrupted hepatic Wnt/β-catenin signalling and zonation...
May 2016: Nature Cell Biology
Douglas Taupin, Wesley Lam, David Rangiah, Larissa McCallum, Belinda Whittle, Yafei Zhang, Daniel Andrews, Matthew Field, Christopher C Goodnow, Matthew C Cook
We report a germline nonsense mutation within the extracellular domain of the RING finger ubiquitin ligase RNF43, segregating with a severe form of serrated polyposis within a kindred. The finding provides evidence that inherited RNF43 mutations define a familial cancer syndrome.
2015: Human Genome Variation
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