Zinc Finger Protein CTCF Regulates Extracellular Matrix (ECM)-Related Gene Expression Associated With the Wnt Signaling Pathway in Gastric Cancer

Liu, Chenbin; Deng, Linyi; Lin, Jinrong; Zhang, Jianjun; Huang, Shu Pin; Zhao, Jinglin; Jin, Peipei; Xu, Peiqing; Ni, Peihong; Xu, Dakang; Ying, Le; Hu, Yiqun

doi:10.3389/fonc.2020.625633

Cited by 14 publications

(14 citation statements)

References 38 publications

(33 reference statements)

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“…Our study identified the TME-related gene PLXDC2 in a highstromal population and had a prognostic signature correlated to the CD163 M2 macrophages, further promoting EMT markers. Similar to the previous reporting that stromal EMT gene signature affects GC prognosis and immunotherapy responsiveness (Zheng and Li, 2020;Liu et al, 2021). The combined PLXDC2/EMT/M2 macrophages axis may affect GC outcome and immunotherapy responsiveness.…”

Section: Discussionsupporting

confidence: 88%

“…Our study confirmed this previous finding and identified a new EMT-related function for PLXDC2. Epithelial-mesenchymal transition in GC have been discussed in previous studies of our lab, and this study extended our understanding of EMT in GC (Liu et al, 2021). The function of our key gene in EMT may indicate that PLXDC2 is a regulator of tumor metastasis.…”

Section: Discussionsupporting

confidence: 69%

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Overexpression of PLXDC2 in Stromal Cell-Associated M2 Macrophages Is Related to EMT and the Progression of Gastric Cancer

Guan

Wang

et al. 2021

Front. Cell Dev. Biol.

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The tumor microenvironment (TME) comprises distinct cell types, including stromal types such as fibroblast cells and macrophage cells, which have recently become a critical factor in tumor development and progression. Here, we identified the TME-related gene, plexin domain containing 2 (PLXDC2), in a high-stromal-score population. And we revealed that this gene was related to poor survival and advanced (tumor-node-metastasis) stage in gastric cancer (GC) patients from The Cancer Genome Atlas database. An integrated gene profile and functional analysis of the proportions of tumor-infiltrating immune cells revealed that the expression of the M2 macrophages cell marker CD163 was positively correlated with PLXDC2 expression. In addition, the M2 macrophages gene signature and high PLXDC2 expression were associated with the inflammatory signaling pathway and the epithelial-to-mesenchymal transition (EMT)-related gene signature. Single-cell study of GC identified PLXDC2 was enriched specifically in fibroblasts and monocytes/macrophages populations, which supported its important role in the stroma. Furthermore, according to a tissue microarray immunohistochemistry analysis, the expression of PLXDC2 elevated in human GC stromal specimens compared to tumor tissue specimens. Moreover, PLXDC2 overexpression in the stromal compartment was associated with CD163-positive regulatory M2 macrophages, and its functions were related to the pathogenesis of GC. Multiplexed immunohistochemistry verified PLXDC2’s correlation with EMT markers. Our data suggested that PLXDC2 was expressed in stromal cells and that its crosstalk with tumor-associated macrophages could contribute to cancer biology by inducing the EMT process.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 69%

Overexpression of PLXDC2 in Stromal Cell-Associated M2 Macrophages Is Related to EMT and the Progression of Gastric Cancer

Guan

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…Liu et al 20 found that high or low expression of ECMrelated genes revealed different levels of tumour aggressiveness, and the zinc finger protein CTCF regulates ECM-related genes, thereby promoting GC cell growth and migration. Wei et al 21 found that HOTAIR and COL5A1 were overexpressed in GC compared to normal controls, and HOTAIR regulates GC growth by sponging miR-1277-5p and upregulating COL5A1 via effects on the tumour microenvironment.…”

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confidence: 99%

Extracellular Matrix-Associated Pathways Promote the Progression of Gastric Cancer by Impacting the Dendritic Cell Axis

Wang¹,

Wang²,

Hu³

et al. 2021

IJGM

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Background: Gastric cancer (GC) is the third most frequent malignant tumour in the Chinese population, let alone the whole world. Recently, most prognostic models have only focused on the levels of several genes, miRNAs, lncRNAs, gene mutations, or DNA methylation; however, the activation status of biological pathways is more stable and can reflect the comprehensive inner conditions of tumours. Methods: We collected samples from the Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) cohort and GSE62254 cohort, with a total of 594 patients. We employed GSEA to first compare the diverse activated signalling pathways between dead GC patients and living patients. The least absolute shrinkage and selection operator (LASSO) regression analysis was subsequently performed by the "glmnet" package to generate a prognostic signature.Results: We extracted a total of 218 genes from the KEGG Focal Adhesion and KEGG ECM Receptor Interaction pathways, which showed significant activation in dead GC patients in two enrolled cohorts, for subsequent LASSO analysis. In the TCGA-STAD cohort, patients in the high-risk group faced a significantly poorer prognosis than those in the low-risk group (P < 0.001, HR: 4.62, 95% CI: 3.447-6.183), with an AUC of 0.694. In the GSE62254 cohort, the HR value was 4.94 (95% CI: 3.413-7.165), and the AUC value was as high as 0.834. A high-risk score and poor prognosis correlated with infiltrated dendritic cells, and the receptor of IFN-α was also positively linked with the risk score, as well as poor prognosis. GC patients with high-risk scores were more likely to respond to CTLA4 treatment but not PD1 treatment. Conclusion: Taken together, we established and verified an extracellular matrix prognostic model of gastric cancer patients. The model can be used to evaluate the risk of death of GC patients, as well as the response to anti-CTLA4 immunotherapy.

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“…Collagen type I α 1 (COL1A1) is a member of collagen family and collagen is the most abundant protein of extracellular matrix (ECM) being naturally present in human tissues such as skin, bones, cartilage, tendon and ligaments. This biopolymer interacts with cells and regulates cell anchorage, migration, proliferation and survival ( 16 , 17 ). In the cardiovascular system, COL1A1 and its related signaling pathways are primarily associated with cardiac development and a variety of diseases processes.…”

Section: Introductionmentioning

confidence: 99%

Parathyroid Hormone Promotes Human Umbilical Vein Endothelial Cell Migration and Proliferation Through Orai1-Mediated Calcium Signaling

Wang

et al. 2022

Front. Cardiovasc. Med.

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Parathyroid hormone is the main endocrine regulator of extracellular calcium and phosphorus levels. Secondary hyperparathyroidism–induced endothelial dysfunction may be related to calcium homeostasis disorders. Here, we investigated the effects of parathyroid hormone on human umbilical vein endothelial cells (HUVECs) and characterized the involvement of store-operated Ca2+ entry (SOCE) and the nuclear factor of activated T cells (NFAT) signaling pathway. We used immunoblot experiments to find that parathyroid hormone significantly enhanced the expression of the Orai1 channel, a type of channel mediating SOCE, SOCE activity, and Orai1-mediated proliferation of HUVECs but did not increase Orai2 and Orai3. RNA-seq was utilized to identify 1,655 differentially expressed genes (823 upregulated and 832 downregulated) in parathyroid hormone–treated HUVECs as well as enhanced focal adhesion signaling and expression levels of two key genes, namely, COL1A1 and NFATC1. Increased protein and mRNA expression levels of COL1A1 and NFATC1 were confirmed by immunoblotting and quantitative RT-PCR, respectively. Cytosol and nuclei fractionation experiments and immunofluorescence methods were used to show that parathyroid hormone treatment increased NFATC1 nuclear translocation, which was inhibited by a calcineurin inhibitor (CsA), a selective calmodulin antagonist (W7), an Orai channel inhibitor (BTP2), or Orai1 small interfering RNA (siRNA) transfection. Parathyroid hormone also increased COL1A1 expression, cell migration, and proliferation of HUVECs. The PTH-induced increase in HUVEC migration and proliferation were inhibited by CsA, W7, BTP2, or COL1A1 siRNA transfection. These findings indicated that PTH increased Orai1 expression and Orai1-mediated SOCE, causing the nuclear translocation of NFATC1 to increase COL1A1 expression and COL1A1-mediated HUVEC migration and proliferation. These results suggest potential key therapeutic targets of Orai1 and the downstream calmodulin/calcineurin/NFATC1/COL1A1 signaling pathway in parathyroid hormone–induced endothelial dysfunction and shed light on underlying mechanisms that may be altered to prevent or treat secondary hyperparathyroidism–associated cardiovascular disease.

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Zinc Finger Protein CTCF Regulates Extracellular Matrix (ECM)-Related Gene Expression Associated With the Wnt Signaling Pathway in Gastric Cancer

Cited by 14 publications

References 38 publications

Overexpression of PLXDC2 in Stromal Cell-Associated M2 Macrophages Is Related to EMT and the Progression of Gastric Cancer

Overexpression of PLXDC2 in Stromal Cell-Associated M2 Macrophages Is Related to EMT and the Progression of Gastric Cancer

Extracellular Matrix-Associated Pathways Promote the Progression of Gastric Cancer by Impacting the Dendritic Cell Axis

Parathyroid Hormone Promotes Human Umbilical Vein Endothelial Cell Migration and Proliferation Through Orai1-Mediated Calcium Signaling

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