<scp>SPHK</scp>1‐induced autophagy in peritoneal mesothelial cell enhances gastric cancer peritoneal dissemination

Yin, Saifu; Zhang, Miao; Tan, Yongjun; Wang, Pengliang; Xu, Xiaoyu; Zhang, Chao; Hou, Wenting; Huang, Jinyu; Xu, Hui

doi:10.1002/cam4.2041

Cited by 32 publications

(29 citation statements)

References 36 publications

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“…In GSEA enrichment, cancerrelated pathways, such as the TGF-β, MAPK and JAK2 signaling pathways, were signi cantly identi ed. Notably, our previous study showed that TGF-β was an independent factor of the peritoneal metastasis of GC [30]. These results reveal the deeper mechanism of COL5A2 in the metastasis development of GC.…”

Section: Discussionmentioning

confidence: 56%

The TCGA and GEO databases identify COL5A2 as a poorly prognostic gene in patients with advanced gastric cancer

Tan

Chen

Xing

et al. 2020

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Background Gastric cancer (GC) metastasis determines the prognosis of patients, and exploring the molecular mechanism of GC metastasis is expected to provide a theoretical basis for clinical treatment. Recent studies have shown that extracellular matrix protein is closely related to GC metastasis. This study aimed to explore the expression profile and role of COL5A2 (Collagen V-type α2), as an extracellular matrix protein, in GC. Methods The expression, overall survival and progression-free survival data of COL5 family members were extracted from The Cancer Genome Atlas(TCGA)database, respectively. Paraffin immunohistochemistry and RT-qPCR in GC and matched normal tissues were used to analyze the expression of the target genes. Weighted gene co-expression network analysis of the GSE62229 database was performed out to identify modules and associated genes, and the functions were predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Results COL5A2 was selected as our research target in the TCGA database, and was also verified in the GSE62229 and GSE15459 datasets. COL5A2 was upregulated in GC tissues by paraffin immunohistochemistry and RT-qPCR. The analysis of clinicopathological characteristics showed a significant difference in the Borrmann type (P = 0.036), histological type (P = 0.013) and T stage(P = 0.011). The prognosis of patients with low COL5A2 expression was better than that of patients with high COL5A2 expression. GSEA results showed that the TCGA and GSE62229 samples were significantly enriched in several well-known cancer-related pathways, such as the TGF-β, MAPK, and JAK2 signaling pathways. Conclusion COL5A2 was most closely related to advanced GC among COL5 family members. High COL5A2 expression is associated with a poor prognosis in GC, and may be a novel therapeutic target for GC.

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Section: Discussionmentioning

confidence: 56%

The TCGA and GEO databases identify COL5A2 as a poorly prognostic gene in patients with advanced gastric cancer

Tan

Chen

Xing

et al. 2020

Preprint

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“…On the one hand, it can remove damaged organelles and proteins to maintain homeostasis of the intracellular environment. On the other hand, it can be associated with cell proliferation, the promotion of apoptosis, or promotion of brotic changes in the morphology and behavior of epithelial cells (27), (28) .…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Autophagy Axis Induces VEGFA by Peritoneal Mesothelial Cells to Promote Gastric Cancer Peritoneal Metastasis Through an Integrin α5-Fibronectin Pathway

Wang¹,

Che²,

Yu³

et al. 2020

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Background: Peritoneal metastasis (PM) is an important pathological process in the progression of gastric cancer (GC). The metastatic potential of tumor and stromal cells is governed by hypoxia, which is a key molecular feature of the tumor microenvironment. Mesothelial cells also participate in this complex and dynamic process. However, the molecular mechanisms underlying the hypoxia-driven mesothelial-tumor interactions that promote peritoneal metastasis of GC remain unclear.Methods: We determined the hypoxic microenvironment in PM of nude mice by immunohistochemical analysis and screened VEGFA by human growth factor array kit. The crosstalk mediated by VEGFA between peritoneal mesothelial cells (PMCs) and GC cells was determined in GC cells incubated with conditioned medium prepared from hypoxia-treated PMCs. The association between VEGFR1 and integrin α5 and fibronectin in GC cells was enriched using Gene Set Enrichment Analysis and KEGG pathway enrichment analysis. In vitro and xenograft mouse models were used to evaluate the impact of VEGFA/VEGFR1 on gastric cancer peritoneal metastasis. Confocal microscopy and immunoprecipitation were performed to determine the effect of hypoxia-induced autophagy.Results: Here we report that in the PMCs of the hypoxic microenvironment, SIRT1 is degraded via the autophagic lysosomal pathway, leading to increased acetylation of HIF-1α and secretion of VEGFA. Under hypoxic conditions, VEGFA derived from PMCs acts on VEGFR1 of GC cells, resulting in p-ERK/p-JNK pathway activation, increased integrin α5 and fibronectin expression, and promotion of PM.Conclusions: Our findings have elucidated the mechanisms by which PMCs promote PM in GC in hypoxic environments. This study also provides a theoretical basis for considering autophagic pathways or VEGFA as potential therapeutic targets to treat PM in GC.

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“…This gene has been reported to be tightly associated to autophagy process in several cell types. The previous study has been demonstrated that Sphk1 was capable of promoting autophagy in human peritoneal mesothelial cells (HPMCs), and this process aided the adhesion and invasion of HPMCs [17]. Wang and co-workers demonstrated that microRNA-506-3p was able to inhibit autophagy through targeting Sphk1 in osteosarcoma cells [22].…”

Section: Sphk1 Gene Plays An Important Role In a Variety Of Diseasesmentioning

confidence: 99%

“…Sphk1 gene plays an important role in the regulation of autophagy in several cell types [17], and this gene was also reported to be associated with coronary artery disease [18]. Therefore, it is interesting to probe the effects of Sphk1 on autophagy in H9C2 cells.…”

Section: Evaluation Of Transduce Efficiency Of Ad-sphk1 and Ad-shsphk1mentioning

confidence: 99%

Sphk1 involves in the regulation of autophagy process in cardiac myocyte cells at high glucose condition

Xie

et al. 2019

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Diabetic cardiomyopathy is the myocardium disorders caused by diabetes mellitus, which has become a key concern bringing heavy burden to the public health. Autophagy is one of activities involving in the pathogenesis of diabetic cardiomyopathy. Sphk1 gene plays a crucial role in cell survival and growth, and regulation of many diseases including diabetes and cardiovascular disease. However, the pathogenesis of diabetic cardiomyopathy remains poorly understood. To this aim, the study established adenovirus vectors expressing Sphk1 and shSphk1 to investigate the effects of Sphk1 on autophagy and cell survival in myocardial cells under high glucose conditions (25 mM). It was found that overexpression of Sphk1 promoted autophagy activity in H9c2 cells under high glucose treatment measured by various methodologies including qRT-PCR, western blot, fluorescence microscope, and so on. Inhibition of autophagy decreased cell vitality under high glucose condition. A broadly used medicine silibinin was demonstrated to induce autophagy in a dose-dependent manner. Herein, the findings in the present study may provide useful reference for unveiling the pathogenesis of diabetic cardiomyopathy and developing novel therapies treating diabetic cardiomyopathy.

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SPHK1‐induced autophagy in peritoneal mesothelial cell enhances gastric cancer peritoneal dissemination

Cited by 32 publications

References 36 publications

The TCGA and GEO databases identify COL5A2 as a poorly prognostic gene in patients with advanced gastric cancer

The TCGA and GEO databases identify COL5A2 as a poorly prognostic gene in patients with advanced gastric cancer

Hypoxia-Autophagy Axis Induces VEGFA by Peritoneal Mesothelial Cells to Promote Gastric Cancer Peritoneal Metastasis Through an Integrin α5-Fibronectin Pathway

Sphk1 involves in the regulation of autophagy process in cardiac myocyte cells at high glucose condition

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