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https://www.readbyqxmd.com/read/28600110/rspo2-suppresses-colorectal-cancer-metastasis-by-counteracting-the-wnt5a-fzd7-driven-noncanonical-wnt-pathway
#1
Xiaoming Dong, Wanqin Liao, Li Zhang, Xi Tu, Jin Hu, Tianke Chen, Xiaowei Dai, Yan Xiong, Weicheng Liang, Chaodong Ding, Rui Liu, Juji Dai, Ouchen Wang, Liting Lu, Xincheng Lu
R-spondins play critical roles in development, stem cell survival, and tumorigenicity by modulating Wnt/β-catenin signaling; however, the role of R-spondins in noncanonical Wnt signaling regulation remains largely unknown. We demonstrate here that R-spondin 2 (RSPO2) has an inhibitory effect on colorectal cancer (CRC) cell migration, invasion, and metastasis. Reduced RSPO2 expression was associated with tumor metastasis and poor survival in CRC patients. The metastasis-suppressive activity of RSPO2 was independent of the Wnt/β-catenin signaling pathway but dependent on the Fzd7-mediated noncanonical Wnt signaling pathway...
June 6, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28543708/comprehensive-characterization-of-rspo-fusions-in-colorectal-traditional-serrated-adenomas
#2
Shigeki Sekine, Reiko Ogawa, Taiki Hashimoto, Motohiro Kojima, Hiroshi Yoshida, Hirokazu Taniguchi, Yutaka Saito, Yasuhiro Ohno, Atsushi Ochiai, Nobuyoshi Hiraoka
AIMS: Traditional serrated adenoma (TSA) is a rare but distinct type of colorectal polyp. Our previous study showed that PTPRK-RSPO3 fusions are frequent and characteristic genetic alterations in TSAs. This study aimed to comprehensively characterize the prevalence and variability of RSPO fusions in colorectal TSAs. METHODS AND RESULTS: We examined RSPO expression and explored novel RSPO fusions in 129 TSAs, including 66 lesions previously analyzed for WNT pathway gene mutations...
May 24, 2017: Histopathology
https://www.readbyqxmd.com/read/28472820/clinical-value-of-r-spondins-in-triple-negative-and-metaplastic-breast-cancers
#3
F Coussy, F Lallemand, S Vacher, A Schnitzler, W Chemlali, M Caly, A Nicolas, S Richon, D Meseure, R El Botty, L De-Plater, L Fuhrmann, T Dubois, S Roman-Roman, V Dangles-Marie, E Marangoni, I Bièche
BACKGROUND: RSPO ligands, activators of the Wnt/β-catenin pathway, are overexpressed in different cancers. The objective of this study was to investigate the role of RSPOs in breast cancer (BC). METHODS: Expression of RSPO and markers of various cancer pathways were measured in breast tumours and cell lines by qRT-PCR. The effect of RSPO on the Wnt/β-catenin pathway activity was determined by luciferase assay, western blotting, and qRT-PCR. The effect of RSPO2 inhibition on proliferation was determined by using RSPO2 siRNAs...
June 6, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28350845/abnormal-expression-of-mrna-microrna-alteration-and-aberrant-dna-methylation-patterns-in-rectal-adenocarcinoma
#4
Yang Hua, Xiukun Ma, Xianglong Liu, Xiangfei Yuan, Hai Qin, Xipeng Zhang
AIM: Rectal adenocarcinoma (READ) is a malignancy cancer with the high morbidity and motility worldwide. Our study aimed to explore the potential pathogenesis of READ through integrated analysis of gene expression profiling and DNA methylation data. METHODS: The miRNA, mRNA expression profiling and corresponding DNA methylation data were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed mRNAs/ miRNAs/methylated regions (DEmRNA/DEmiRNAs) were identified in READ...
2017: PloS One
https://www.readbyqxmd.com/read/28219935/novel-insights-into-gastric-cancer-methylation-of-r-spondins-and-regulation-of-lgr5-by-sp1
#5
Franziska Wilhelm, Eva Simon, Christine Böger, Hans-Michael Behrens, Sandra Krüger, Christoph Röcken
Recently, it was shown that leucine-rich repeat-containing receptor 5 (LGR5)-expressing stem cells are the cellular origin of intestinal-type gastric cancer. The aim of our study was to uncover regulatory mechanisms of LGR5 expression in gastric mucosa and their implications for cancer development. Reporter assays identified an LGR5 promoter fragment, which is highly relevant for active LGR5 expression. Chromatin immunoprecipitation verified that SP1 is bound within this region, and reporter activity increased in SP1 transfected cells...
June 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/27809465/identification-of-growth-trait-related-genes-in-a-yorkshire-purebred-pig-population-by-genome-wide-association-studies
#6
Qingli Meng, Kejun Wang, Xiaolei Liu, Haishen Zhou, Li Xu, Zhaojun Wang, Meiying Fang
OBJECTIVE: The aim of this study is to identify genomic regions or genes controlling growth traits in pigs. METHODS: Using a panel of 54,148 single nucleotide polymorphisms (SNPs), we performed a genome-wide Association (GWA) study in 562 pure Yorshire pigs with four growth traits: average daily gain from 30 kg to 100 kg or 115 kg, and days to 100 kg or 115 kg. Fixed and random model Circulating Probability Unification method was used to identify the associations between 54,148 SNPs and these four traits...
April 2017: Asian-Australasian Journal of Animal Sciences
https://www.readbyqxmd.com/read/27767183/molecular-characterization-of-thy1-expressing-fear-inhibiting-neurons-within-the-basolateral-amygdala
#7
Kenneth M McCullough, Dennis Choi, Jidong Guo, Kelsey Zimmerman, Jordan Walton, Donald G Rainnie, Kerry J Ressler
Molecular characterization of neuron populations, particularly those controlling threat responses, is essential for understanding the cellular basis of behaviour and identifying pharmacological agents acting selectively on fear-controlling circuitry. Here we demonstrate a comprehensive workflow for identification of pharmacologically tractable markers of behaviourally characterized cell populations. Thy1-eNpHR-, Thy1-Cre- and Thy1-eYFP-labelled neurons of the BLA consistently act as fear inhibiting or 'Fear-Off' neurons during behaviour...
October 21, 2016: Nature Communications
https://www.readbyqxmd.com/read/27571704/rspo2-suppresses-cd36-mediated-apoptosis-in-oxidized-low-density-lipoprotein-induced-macrophages
#8
Hui Yan, Shuai Wang, Zhenwei Li, Zewei Sun, Jie Zan, Wenting Zhao, Yanyun Pan, Zhen Wang, Mingjie Wu, Jianhua Zhu
Oxidized low density lipoprotein (oxLDL)-induced apoptosis of macrophages contributes to the formation of atherosclerotic plaques. R‑spondin 2 (Rspo2), a member of the cysteine‑rich secreted proteins, has been shown to be involved in the oncogenesis of several types of cancer. It has also been found to be abundantly expressed among the four R‑spondin members in macrophages. The present study was performed to determine whether Rspo2 is involved in the ox‑LDL‑induced apoptosis of macrophages. It was identified that Rspo2 inhibited oxLDL‑induced apoptosis in the presence of endoplasmic reticulum (ER) stress activator using flow cytometry...
October 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27511199/rspo3-expands-intestinal-stem-cell-and-niche-compartments-and-drives-tumorigenesis
#9
John Hilkens, Nikki C Timmer, Mandy Boer, Gerjon J Ikink, Matthias Schewe, Andrea Sacchetti, Martijn A J Koppens, Ji-Ying Song, Elvira R M Bakker
OBJECTIVE: The gross majority of colorectal cancer cases results from aberrant Wnt/β-catenin signalling through adenomatous polyposis coli (APC) or CTNNB1 mutations. However, a subset of human colon tumours harbour, mutually exclusive with APC and CTNNB1 mutations, gene fusions in RSPO2 or RSPO3, leading to enhanced expression of these R-spondin genes. This suggested that RSPO activation can substitute for the most common mutations as an alternative driver for intestinal cancer. Involvement of RSPO3 in tumour growth was recently shown in RSPO3-fusion-positive xenograft models...
June 2017: Gut
https://www.readbyqxmd.com/read/27374772/identification-and-functional-characterization-of-rspo2-as-a-susceptibility-gene-for-ossification-of-the-posterior-longitudinal-ligament-of-the-spine
#10
Masahiro Nakajima, Ikuyo Kou, Hirofumi Ohashi, Shiro Ikegawa
Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common spinal disorder that results from ectopic ossification of the posterior longitudinal ligament and causes intractable myelopathy and radiculopathy. In a previous genome-wide association study (GWAS), we found six loci associated with OPLL; however, susceptibility genes in these loci have not been identified yet. Here, we examined one of the GWAS loci and identified RSPO2 (encoding R-spondin 2) as a susceptibility gene for OPLL...
July 7, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27338477/control-of-wnt-receptor-turnover-by-r-spondin-znrf3-rnf43-signaling-module-and-its-dysregulation-in-cancer
#11
REVIEW
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
https://www.readbyqxmd.com/read/27328992/r-spondin-2-promotes-acetylcholine-receptor-clustering-at-the-neuromuscular-junction-via-lgr5
#12
Hiroaki Nakashima, Bisei Ohkawara, Shinsuke Ishigaki, Takayasu Fukudome, Kenyu Ito, Mikito Tsushima, Hiroyuki Konishi, Tatsuya Okuno, Toshiro Yoshimura, Mikako Ito, Akio Masuda, Gen Sobue, Hiroshi Kiyama, Naoki Ishiguro, Kinji Ohno
At the neuromuscular junction (NMJ), acetylcholine receptor (AChR) clustering is mediated by spinal motor neuron (SMN)-derived agrin and its receptors on the muscle, the low-density lipoprotein receptor-related protein 4 (LRP4) and muscle-specific receptor tyrosine kinase (MuSK). Additionally, AChR clustering is mediated by the components of the Wnt pathway. Laser capture microdissection of SMNs revealed that a secreted activator of Wnt signaling, R-spondin 2 (Rspo2), is highly expressed in SMNs. We found that Rspo2 is enriched at the NMJ, and that Rspo2 induces MuSK phosphorylation and AChR clustering...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27314333/n-glycosylation-of-human-r-spondin-1-is-required-for-efficient-secretion-and-stability-but-not-for-its-heparin-binding-ability
#13
Chiung-Fang Chang, Li-Sung Hsu, Chieh-Yu Weng, Chih-Kai Chen, Shu-Ying Wang, Yi-Hwa Chou, Yan-Yu Liu, Zi-Xiu Yuan, Wen-Ying Huang, Ho Lin, Yau-Hung Chen, Jen-Ning Tsai
R-spondin 1 (Rspo1) plays an essential role in stem cell biology by potentiating Wnt signaling activity. Despite the fact that Rspo1 holds therapeutic potential for a number of diseases, its biogenesis is not fully elucidated. All Rspo proteins feature two amino-terminal furin-like repeats, which are responsible for Wnt signal potentiation, and a thrombospondin type 1 (TSR1) domain that can provide affinity towards heparan sulfate proteoglycans. Using chemical inhibitors, deglycosylase and site-directed mutagenesis, we found that human Rspo1 and Rspo3 are both N-glycosylated at N137, a site near the C-terminus of the furin repeat 2 domain, and Rspo2 is N-glycosylated at N160, a position near the N-terminus of TSR1 domain...
June 14, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27216425/crosstalk-between-ahr-and-wnt-%C3%AE-catenin-signal-pathways-in-the-cardiac-developmental-toxicity-of-pm2-5-in-zebrafish-embryos
#14
Hang Zhang, Yugang Yao, Yang Chen, Cong Yue, Jiahong Chen, Jian Tong, Yan Jiang, Tao Chen
Recent studies have shown an association between congenital heart defects and air fine particle matter (PM2.5), but the molecular mechanisms remain elusive. It is well known that a number of organic compounds in PM2.5 can act as AhR agonists, and activation of AhR can antagonize Wnt/β-catenin signaling. Therefore, we hypothesized that PM2.5 could activate AhR and then repress the expression of wnt/β-catenin targeted genes essential for cardiogenesis, resulting in heart defects. To test this hypothesis, we investigated the effects of extractable organic matter (EOM) from PM2...
April 29, 2016: Toxicology
https://www.readbyqxmd.com/read/27158331/rspo2-enriches-lgr5-spheroid-colon-cancer-stem-cells-and-promotes-its-metastasis-by-epithelial-mesenchymal-transition
#15
Shi Zhang, Xiaoyan Han, Bo Wei, Jiafeng Fang, Hongbo Wei
Colon cancer stem cells (CCSCs) account for the tumorigenicity of colon cancer and promote its progression and metastasis. RSPO2, the agonist of canonical Wnt/beta-catenin pathway and serves as the growth factor of intestinal stem cells (ISCs), is considered playing an important role in CCSCs. However, the specific function of RSPO2 in CCSCs remains unclear. In this study, we demonstrated that RSPO2 was highly expressed in CCSCs-enriched HCT116 spheroid cells. Elevates the concentration of RSPO2 in medium in favor of enriching the LGR5(+) cells and increasing the LGR5 expression in HCT116 spheroid cells, meanwhile silencing of RSPO2 by small interfering RNA inhibits LGR5 expression in HCT116 spheroid cells...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27140682/lgr4-acts-as-a-key-receptor-for-r-spondin-2-to-promote-osteogenesis-through-wnt-signaling-pathway
#16
Chao Zhu, Xin-Feng Zheng, Yue-Hua Yang, Bo Li, Yu-Ren Wang, Sheng-Dan Jiang, Lei-Sheng Jiang
R-spondin proteins are identified as secreted agonists of the canonical Wnt/β-catenin signaling pathway, and leucine-rich repeat-containing G-protein-coupled receptors (LGR) are recognized as R-spondin receptors. The potential role of R-spondin 2 (Rspo2) and LGR4 in mediating osteogenesis remains poorly understood. In our in vitro experiments, we found that Rspo2 could promote osteogenesis through activating the Wnt signaling pathway in MC3T3-E1 cells. However, this effect of Rsop2 disappeared in the cells with functional disruption of LGR4...
2016: Cellular Signalling
https://www.readbyqxmd.com/read/27109869/activating-hair-follicle-stem-cells-via-r-spondin2-to-stimulate-hair-growth
#17
Andrew A Smith, Jingtao Li, Bo Liu, Daniel Hunter, Malcolm Pyles, Martin Gillette, Girija R Dhamdhere, Arie Abo, Anthony Oro, Jill A Helms
Wnt signaling is required for the development of the hair follicle, and for inciting the growth (anagen) phase of the hair cycle. Most strategies to enhance Wnt signaling for hair growth create a state of constitutive Wnt activation, which leads to neoplastic transformation of the epithelial hair matrix. Using Axin2(LacZ/+) and Axin2(Cre/+)R26R(mTmG/+) reporter mice and RNA analyses, we show that Wnt signaling is elevated during anagen, is reduced at the onset of catagen, and can be reamplified in the skin and surrounding hair follicles via intradermal injection of recombinant R-spondin2 protein...
August 2016: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/27046199/r-spondins-are-expressed-by-the-intestinal-stroma-and-are-differentially-regulated-during-citrobacter-rodentium-and-dss-induced-colitis-in-mice
#18
Eugene Kang, Mitra Yousefi, Samantha Gruenheid
The R-spondin family of proteins has recently been described as secreted enhancers of β-catenin activation through the canonical Wnt signaling pathway. We previously reported that Rspo2 is a major determinant of susceptibility to Citrobacter rodentium-mediated colitis in mice and recent genome-wide association studies have revealed RSPO3 as a candidate Crohn's disease-specific inflammatory bowel disease susceptibility gene in humans. However, there is little information on the endogenous expression and cellular source of R-spondins in the colon at steady state and during intestinal inflammation...
2016: PloS One
https://www.readbyqxmd.com/read/27012200/r-spondin-2-facilitates-differentiation-of-proliferating-chondrocytes-into-hypertrophic-chondrocytes-by-enhancing-wnt-%C3%AE-catenin-signaling-in-endochondral-ossification
#19
Yasuhiko Takegami, Bisei Ohkawara, Mikako Ito, Akio Masuda, Hiroaki Nakashima, Naoki Ishiguro, Kinji Ohno
Endochondral ossification is a crucial process for longitudinal growth of bones. Differentiating chondrocytes in growth cartilage form four sequential zones of proliferation, alignment into column, hypertrophy, and substitution of chondrocytes with osteoblasts. Wnt/β-catenin signaling is essential for differentiation of proliferating chondrocytes into hypertrophic chondrocytes in growth cartilage. R-spondin 2 (Rspo2), a member of R-spondin family, is an agonist for Wnt signaling, but its role in chondrocyte differentiation remains unknown...
April 22, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/26658453/targeting-the-wnt-%C3%AE-catenin-pathway-in-primary-ovarian-cancer-with-the-porcupine-inhibitor-wnt974
#20
Jonathan D Boone, Rebecca C Arend, Bobbi E Johnston, Sara J Cooper, Scott A Gilchrist, Denise K Oelschlager, William E Grizzle, Gerald McGwin, Abhishek Gangrade, J Michael Straughn, Donald J Buchsbaum
Preclinical studies in ovarian cancer have demonstrated upregulation of the Wnt/β-catenin pathway promoting tumor proliferation and chemoresistance. Our objective was to evaluate the effect of the Wnt/β-catenin pathway inhibitor, WNT974, in primary ovarian cancer ascites cells. Ascites cells from patients with papillary serous ovarian cancer were isolated and treated with 1 μM WNT974±100 μM carboplatin. Viability was evaluated with the ATPlite assay. The IC50 was calculated using a dose-response analysis...
February 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
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