Sorting Nexin 27 as a potential target in G�protein‑coupled receptor recycling for cancer therapy (Review)

Bao, Zixu; Zhou, Shijun; Zhou, Haisheng

doi:10.3892/or.2020.7766

Cited by 6 publications

(7 citation statements)

References 84 publications

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“…G protein-coupled receptors are the largest membrane protein family and are broadly engaged with transduction of multiple intracellular downstream signaling pathways. Binding to the PDZ binding motif of G protein-coupled receptors through PDZ domain, SNX27 interferes with its recycling from the endosome to cell membrane, and thus SNX27 is expected to be the next promising tumor therapeutic target 34 . In general, SNX family members participating in construction of the retromer complex were directly involved in the degradation or cycling of numerous receptors, but other SNXs were also illustrated to regulate intracellular transportation through their distinct domains such as PDZ domain, giving an insight into the reason why aberrant expression of SNX family members affects tumor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Identification of specific role of SNX family in gastric cancer prognosis evaluation

Yin

Sun

2022

Sci Rep

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We here perform a systematic bioinformatic analysis to uncover the role of sorting nexin (SNX) family in clinical outcome of gastric cancer (GC). Comprehensive bioinformatic analysis were realized with online tools such as TCGA, GEO, String, Timer, cBioportal and Kaplan–Meier Plotter. Statistical analysis was conducted with R language or Perl, and artificial neural network (ANN) model was established using Python. Our analysis demonstrated that SNX4/5/6/7/8/10/13/14/15/16/20/22/25/27/30 were higher expressed in GC, whereas SNX1/17/21/24/33 were in the opposite expression profiles. GSE66229 was employed as verification of the differential expression analysis based on TCGA. Clustering results gave the relative transcriptional levels of 30 SNXs in tumor, and it was totally consistent to the inner relevance of SNXs at mRNA level. Protein–Protein Interaction map showed closely and complex connection among 33 SNXs. Tumor immune infiltration analysis asserted that SNX1/3/9/18/19/21/29/33, SNX1/17/18/20/21/29/31/33, SNX1/2/3/6/10/18/29/33, and SNX1/2/6/10/17/18/20/29 were strongly correlated with four kinds of survival related tumor-infiltrating immune cells, including cancer associated fibroblast, endothelial cells, macrophages and Tregs. Kaplan–Meier survival analysis based on GEO presented more satisfactory results than that based on TCGA-STAD did, and all the 29 SNXs were statistically significant, SNX23/26/28 excluded. SNXs alteration contributed to microsatellite instability (MSI) or higher level of MSI-H (hyper-mutated MSI or high level of MSI), and other malignancy encompassing mutation of TP53 and ARID1A, as well as methylation of MLH1.The multivariate cox model, visualized as a nomogram, performed excellently in patients risk classification, for those with higher risk-score suffered from shorter overall survival (OS). Compared to previous researches, our ANN models showed a predictive power at a middle-upper level, with AUC of 0.87/0.72, 0.84/0.72, 0.90/0.71 (GSE84437), 0.98/0.66, 0.86/0.70, 0.98/0.71 (GSE66229), 0.94/0.66, 0.83/0.71, 0.88/0.72 (GSE26253) corresponding to one-, three- and five-year OS and recurrence free survival (RFS) estimation, especially ANN model built with GSE66229 including exclusively SNXs as input data. The SNX family shows great value in postoperative survival evaluation of GC, and ANN models constructed using SNXs transcriptional data manifesting excellent predictive power in both OS and RFS prediction works as convincing verification to that.

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Section: Discussionmentioning

confidence: 99%

Identification of specific role of SNX family in gastric cancer prognosis evaluation

Yin

Sun

2022

Sci Rep

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“…Binding to the PDZ binding motif of G protein-coupled receptors through PDZ domain, SNX27 interferes with its recycling from the endosome to cell membrane, and thus SNX27 is expected to be the next promising tumor therapeutic target. [33] In general, SNX family members participating in construction of the retromer complex were directly involved in the degradation or cycling of numerous receptors, but other SNXs were also illustrated to regulate intracellular transportation through their distinct domains such as PDZ domain, giving an insight into the reason why aberrant expression of SNX family members affects tumor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Identification of Specific Role of SNX Family in Gastric Cancer Prognosis Evaluation

Yin

Sun

2021

Preprint

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Project: We here perform a systematic bioinformatic analysis to uncover the role of SNX family in clinical outcome of gastric cancer (GC). Methods: Comprehensive bioinformatic analysis were realized with online tools such as TCGA, GEO, String, Timer, cBioportal and Kaplan-Meier Plotter. Statistic analysis was conducted with R language, and artificial neural network was constructed using Python.Results: Our analysis demonstrated that SNX4/5/6/7/8/10/13/14/15/16/20/22/25/27/30 were higher expressed in GC, whereas SNX1/17/21/24/33 were in the opposite expression profiles. Clustering results gave the relative transcriptional levels of 30 SNXs in tumor, and it was totally consistent to the inner relevance of SNXs at mRNA level. Protein-Protein Interaction (PPI) map showed closely and complex connection among 33 SNXs. Tumor immune infiltration analysis asserted that SNX1/3/9/18/19/21/29/33, SNX1/17/18/20/21/29/31/33, SNX1/2/3/6/10/18/29/33, and SNX1/2/6/10/17/18/20/29 were strongly correlated with four kinds of survival related TIICs, including Cancer associated fibroblast, endothelial cells, macrophages and Tregs. Kaplan-Meier survival analysis based on GEO presented more satisfactory results than that based on TCGA-STAD did, and all the 29 SNXs were statistically significant, SNX12/23/28 excluded. SNXs alteration contributed to MSI or higher level of MSI-H (hyper-mutated MSI or high level of MSI), and other malignancy such as mutation of TP53, ARID1A and MLH1.The multivariate cox model performed excellently in patients risk classification, for those with higher risk-score suffered from OS period and susceptibility to death as well as tumor immune infiltration. Compared to previous researches, our ANN models shown a predictive power at a middle-upper level, with AUC of 0.87/0.72, 0.84/0.72, 0.90/0.71, 0.94/0.66, 0.83/0.71, 0.88/0.72 corresponding to one-, three- and five-year OS and RFS estimation, but we were totally sure that those models would perform great better if given larger-size samples, which served as evidence to specific role of SNX family in prognosis assessment in GC. Conclusion: The SNX family shows great value in postoperative survival of GC, and artificial neural network models constructed using SNXs transcriptional data manifest excellent predictive power in both OS and RFS evaluation.

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“…Additional studies using mouse models report decreased cell proliferation, tumor growth inhibition, and longer survival times (Frost et al, 2008;Pim et al, 2015). Finally, SNX27 may regulate matrix invasion by recycling specific matrix proteins, such as MT1-MMP metalloprotease, through a direct interaction (Bao et al, 2020;Sharma et al, 2020).…”

Section: Cancersmentioning

confidence: 98%

“…Sorting nexin 27 is increasingly linked to cancers by mediating multiple protein-protein interactions important in trafficking, protein sorting, and membrane remodeling (Clairfeuille et al, 2016). The Cancer Genome Atlas database reveals SNX27 is highly expressed in invasive breast cancer tissue (Zhang et al, 2019;Bao et al, 2020;Sharma et al, 2020). Multiple studies have suggested how SNX27 affects tumor growth both in vitro and in vivo (Zhang et al, 2019;Sharma et al, 2020;Yang et al, 2020).…”

Section: Cancersmentioning

confidence: 99%

Toward Understanding the Molecular Role of SNX27/Retromer in Human Health and Disease

Chandra

Kendall

Jackson

2021

Front. Cell Dev. Biol.

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Aberrations in membrane trafficking pathways have profound effects in cellular dynamics of cellular sorting processes and can drive severe physiological outcomes. Sorting nexin 27 (SNX27) is a metazoan-specific sorting nexin protein from the PX-FERM domain family and is required for endosomal recycling of many important transmembrane receptors. Multiple studies have shown SNX27-mediated recycling requires association with retromer, one of the best-known regulators of endosomal trafficking. SNX27/retromer downregulation is strongly linked to Down’s Syndrome (DS) via glutamate receptor dysfunction and to Alzheimer’s Disease (AD) through increased intracellular production of amyloid peptides from amyloid precursor protein (APP) breakdown. SNX27 is further linked to addiction via its role in potassium channel trafficking, and its over-expression is linked to tumorigenesis, cancer progression, and metastasis. Thus, the correct sorting of multiple receptors by SNX27/retromer is vital for normal cellular function to prevent human diseases. The role of SNX27 in regulating cargo recycling from endosomes to the cell surface is firmly established, but how SNX27 assembles with retromer to generate tubulovesicular carriers remains elusive. Whether SNX27/retromer may be a putative therapeutic target to prevent neurodegenerative disease is now an emerging area of study. This review will provide an update on our molecular understanding of endosomal trafficking events mediated by the SNX27/retromer complex on endosomes.

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Sorting Nexin 27 as a potential target in G�protein‑coupled receptor recycling for cancer therapy (Review)

Cited by 6 publications

References 84 publications

Identification of specific role of SNX family in gastric cancer prognosis evaluation

Identification of specific role of SNX family in gastric cancer prognosis evaluation

Identification of Specific Role of SNX Family in Gastric Cancer Prognosis Evaluation

Toward Understanding the Molecular Role of SNX27/Retromer in Human Health and Disease

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