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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
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...
August 10, 2016: Gut
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
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...
2016: Cancers
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
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...
2016: International Journal of Molecular Sciences
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
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
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...
August 2016: Cellular Signalling
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
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
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
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
Evert-Jan P M Ten Dam, Marike M van Beuge, Ruud A Bank, Paul M N Werker
Genetic background plays an important role in the development of Dupuytren's disease. A genome-wide association study (GWAS) showed that nine loci are associated with the disease, six of which contain genes that are involved in Wnt signaling (WNT2, WNT4, WNT7B, RSPO2, SFRP4, SULF1). To obtain insight in the role of these genes, we performed expression studies on affected and unaffected patient's tissues. Surgically obtained nodules and cords from eight Dupuytren's patients were compared to patient-matched control tissue (unaffected transverse palmar fascia)...
March 2016: Journal of Cell Communication and Signaling
Gregory Michelotti, Xiaoyin Jiang, Julie Ann Sosa, Anna Mae Diehl, Brittany Bohinc Henderson
PURPOSE: Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a cancer stem cell marker and a down-stream target in Wnt/β-catenin signaling. In human papillary thyroid cancer (PTC), over activation of Wnt/β-catenin has been associated with tumor aggressiveness. PATIENTS AND METHODS: Using established human cell lines (TPC-1, KTC-1, Nthy-ori-3-1), we report LGR5 and R-spondin (RSPO1-3) overexpression in PTC and manipulate LGR5 and Wnt/β-catenin signaling via both pharmacologic and genetic interventions...
October 27, 2015: Oncotarget
Barbara G Schneider, Robertino Mera, M Blanca Piazuelo, Juan C Bravo, Jovanny Zabaleta, Alberto G Delgado, Luis E Bravo, Keith T Wilson, Wael El-Rifai, Richard M Peek, Pelayo Correa
BACKGROUND: Development of the intestinal subtype of gastric adenocarcinoma is marked by a progression of histopathologic lesions. Residents of the Andean regions of Colombia are at high risk for gastric cancer. METHODS: A cohort of 976 Colombian subjects was followed over 16 years examining effects of Helicobacter pylori eradication and treatment with antioxidants on progression of lesions. We performed methylation analysis of DNA from baseline antral biopsies from 104 subjects for whom follow-up data were available for at least 12 years...
October 2015: Cancer Epidemiology, Biomarkers & Prevention
Matthias Zebisch, E Yvonne Jones
The four secreted R-spondin (Rspo1-4) proteins of vertebrates function as stem cell growth factors and potentiate canonical Wnt signalling. Rspo proteins act by cross-linking members of two cell surface receptor families, complexing the stem cell markers LGR4-6 with the Frizzled-specific E3 ubiquitin ligases ZNRF3/RNF43. The consequent internalisation of the ternary LGR-Rspo-E3 complex removes the E3 ligase activity, which otherwise targets the Wnt receptor Frizzled for degradation, and thus enhances Wnt signalling...
August 2015: Journal of Structural Biology
Su-Chen Li, Hao Shi, Mohid Khan, Martyn Caplin, Tim Meyer, Kjell Öberg, Valeria Giandomenico
This study aims at investigating miR-196a roles using in vitro models. miR-196a was detected in small intestinal neuroendocrine tumors (SI-NETs) and lung NETs. miR-196a target prediction analysis suggested HOXA9, HOXB7, LRP4 and RSPO2 genes for further investigation. The level of these four genes is detectable in SI-NET tissue specimens at different disease stages and serum samples of untreated and somatostatin analogs treated patients with liver metastases. A miR-196a inhibitor was used to silence its effects in NET cells...
September 5, 2015: Molecular and Cellular Endocrinology
Babita Madan, David M Virshup
Wnt signaling is dysregulated in many cancers and is therefore an attractive therapeutic target. The focus of drug development has recently shifted away from downstream inhibitors of β-catenin. Active inhibitors of Wnt secretion and Wnt/receptor interactions have been developed that are now entering clinical trials. Such agents include inhibitors of Wnt secretion, as well as recombinant proteins that minimize Wnt-Frizzled interactions. These new therapies arrive together with the recent insight that cancer-specific upregulation of Wnt receptors at the cell surface regulates cellular sensitivity to Wnts...
May 2015: Molecular Cancer Therapeutics
Matthias Ilmer, Alejandro Recio Boiles, Ivonne Regel, Kenji Yokoi, Christoph W Michalski, Ignacio I Wistuba, Jaime Rodriguez, Eckhard Alt, Jody Vykoukal
Cancer stem cells (CSC) present a formidable clinical challenge by escaping therapeutic intervention and seeding tumors through processes that remain incompletely understood. Here, we describe small subpopulations of pancreatic cancer cells with high intrinsic Wnt activity (Wnt(high)) that possess properties indicative of CSCs, including drug resistance and tumor-initiating capacity, whereas cell populations with negligible Wnt activity (Wnt(low)) preferentially express markers of differentiation. Spontaneous response to extrinsic Wnt signals induces signaling networks comprising ERK1/2 and epithelial-mesenchymal transition that subsequently confer cancer stemness traits to susceptible cells...
May 1, 2015: Cancer Research
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