Robo4 is constitutively shed by ADAMs from endothelial cells and the shed Robo4 functions to inhibit Slit3-induced angiogenesis

Xiao, Wenyuan; Pinilla-Baquero, Alejandro; Song, Xuehong; Prabhakar, Pradeep Kumar; Qiu, Hong; Moremen, Kelley W.; Ludwig, Andreas; Dempsey, Peter J.; Azadi, Parastoo; Wang, Lianchun

doi:10.1038/s41598-022-08227-8

Cited by 6 publications

(8 citation statements)

References 38 publications

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“…In ADAM17flox/flox/Tie2-Cre mice, loss of endothelial ADAM17 inhibits chord formation and impedes ectopic injected tumor growth (138). In endothelial cells, soluble Robo4 (sRobo4) is shed and released by ADAM1, which subsequently inhibits SLIT3-induced angiogenesis (248). Meanwhile, SLIT3 obstructs Robo4 shedding and enhances its signal transduction (248).…”

Section: Regulation Of Endothelial Cells By Adam17mentioning

confidence: 99%

“…In endothelial cells, soluble Robo4 (sRobo4) is shed and released by ADAM1, which subsequently inhibits SLIT3-induced angiogenesis (248). Meanwhile, SLIT3 obstructs Robo4 shedding and enhances its signal transduction (248). ADAM17 may disrupt the barrier effect of vascular endothelial cells by affecting their attachment and tight junctions (249).…”

Section: Regulation Of Endothelial Cells By Adam17mentioning

confidence: 99%

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Immunomodulatory role of metalloproteinase ADAM17 in tumor development

et al. 2022

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ADAM17 is a member of the a disintegrin and metalloproteinase (ADAM) family of transmembrane proteases involved in the shedding of some cell membrane proteins and regulating various signaling pathways. More than 90 substrates are regulated by ADAM17, some of which are closely relevant to tumor formation and development. Besides, ADAM17 is also responsible for immune regulation and its substrate-mediated signal transduction. Recently, ADAM17 has been considered as a major target for the treatment of tumors and yet its immunomodulatory roles and mechanisms remain unclear. In this paper, we summarized the recent understanding of structure and several regulatory roles of ADAM17. Importantly, we highlighted the immunomodulatory roles of ADAM17 in tumor development, as well as small molecule inhibitors and monoclonal antibodies targeting ADAM17.

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Section: Regulation Of Endothelial Cells By Adam17mentioning

confidence: 99%

Section: Regulation Of Endothelial Cells By Adam17mentioning

confidence: 99%

Immunomodulatory role of metalloproteinase ADAM17 in tumor development

et al. 2022

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“…Taken together, the results of the RNA-seq bioinformatic analysis, qRT-PCR validation, and IHC confirmed that SLIT3 may be involved in regulating angiogenesis of EP villi. Next, we validated the target gene ROBO4 ( Xiao et al., 2022 ), which is downstream of SLIT3 and reportedly associated with angiogenesis, via qRT-PCR. This assay indicated that relative expression of ROBO4 was statistically lower in EP than in NP villous tissue ( p = 0.007) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Another study revealed that SLIT2 is expressed in extravillous trophoblasts (EVTs) of tubal pregnancy, and that changes in SLIT2 expression are linked to vascular remodeling of the fallopian tube ( Li et al., 2015 ). SLIT3 is a new angiogenic factor that binds to ROBO4 , promoting endothelial cell proliferation and migration and inducing angiogenesis in vivo ( Xiao et al., 2022 ; Zhang et al., 2009 ). Moreover, expression of ROBO4 in placental arteries and veins ( Huminiecki et al., 2002 ) and of SLIT3 in the placenta ( Dickinson et al., 2004 ) have been previously reported.…”

Section: Discussionmentioning

confidence: 99%

Abnormal expression of SLIT3 induces intravillous vascularization dysplasia in ectopic pregnancy

Zhu

Zhao

Zhang

et al. 2023

PeerJ

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Objective To investigate whether the morphology, capillary number, and transcriptome expression profiles of ectopic pregnancy (EP) villi differ from those of normal pregnancy (NP) villi. Methods Hematoxylin-eosin (HE) and immunohistochemistry (IHC) staining for CD31 were conducted to compare differences in morphology and capillary number between EP and NP villi. Differentially expressed (DE) miRNAs and mRNAs were determined from transcriptome sequencing of both types of villi and used to construct a miRNA–mRNA network, from which hub genes were identified. Candidate DE-miRNAs and DE-mRNAs were validated by quantitative reverse transcription (qRT)-PCR. Correlations were identified between the number of capillaries and serum beta human chorionic gonadotropin (β-HCG) levels and between the expression levels of hub genes associated with angiogenesis and β-HCG levels. Results The mean and total cross-sectional areas of placental villi were significantly increased in EP compared with NP villi. Capillary density was greatly reduced in EP villi and was positively correlated with β-HCG levels. A total of 49 DE-miRNAs and 625 DE-mRNAs were identified from the sequencing data. An integrated analysis established a miRNA–mRNA network containing 32 DE-miRNAs and 103 DE-mRNAs. Based on the validation of hub mRNAs and miRNAs in the network, a regulatory pathway involving miR-491-5p–SLIT3 was discovered, which may have a role in the development of villous capillaries. Conclusion Villus morphology, capillary number, and miRNA/mRNA expression profiles in villous tissues were aberrant in EP placentas. Specifically, SLIT3, which is regulated by miR-491-5p, may contribute to the regulation of villous angiogenesis and was established as a putative predictor of chorionic villus development, providing a basis for future research.

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“…To date, no research on ROBO4 and pancreatic cancer appears to have been conducted. Numerous studies have shown that ROBO4 stabilizes the vascular network under normal circumstances, which prevents the vasculature from leaking (41)(42)(43). ROBO4 had an effect in various cancers by promoting angiogenesis (44,45).…”

Section: Gene Ratiomentioning

confidence: 99%

Development of a basement membrane gene signature and identification of the potential candidate therapeutic targets for pancreatic cancer

Lin¹,

Xu²,

Wang³

et al. 2023

Gland Surg

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Background: Pancreatic cancer is a deadly cancer with a poor prognosis. In light of mounting evidence that basement membrane genes (BMGs) play a role in the development of cancer, we sought to examine the prognostic importance and role of BMGs in pancreatic ductal adenocarcinoma (PDAC) patients.Methods: BMGs were obtained from previous top research studies. The clinical and messenger ribonucleic acid expression data were retrieved from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data sets, respectively. Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were used for the PDAC risk modeling and gene identification. The Kaplan-Meier method was used to compare outcomes between the low-and high-risk groups. Finally, we analyzed small-molecule drugs that could be used to target BMGs for treatment using the Enrichr data set and validated the function of the tubulointerstitial nephritis antigen (TINAG) in pancreatic cancer.Results: We successfully constructed and validated a 7 BMG-based model to predict PDAC patient outcomes. Additionally, we discovered that 7 BMG-based model was an independent predictive factor for PDAC. According to our functional analysis, the majority of the signaling pathways enriched in BMGs were those connected to malignancy. Immune cell infiltration and immunological checkpoints were also linked to the BMG-based model. Further, we identified 5 small-molecule drugs that may be useful in treating PDAC patients. We also found that TINAG promoted cell proliferation in pancreatic cancer.Conclusions: Our study extended understandings of how BMGs work in PDAC. We identified a credible predictive biomarker for PDAC patients' survival.

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Robo4 is constitutively shed by ADAMs from endothelial cells and the shed Robo4 functions to inhibit Slit3-induced angiogenesis

Cited by 6 publications

References 38 publications

Immunomodulatory role of metalloproteinase ADAM17 in tumor development

Immunomodulatory role of metalloproteinase ADAM17 in tumor development

Abnormal expression of SLIT3 induces intravillous vascularization dysplasia in ectopic pregnancy

Development of a basement membrane gene signature and identification of the potential candidate therapeutic targets for pancreatic cancer

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