Dataset Information

GALC Triggers Tumorigenicity of Colorectal Cancer via Senescent Fibroblasts.

ABSTRACT: Colorectal cancer (CRC)-associated senescent fibroblasts may play a crucial role in tumor progression, but the mechanism remains unclear. In order to solve this complicated problem, we randomly collected 16 patients with CRC, who had been treated with oxaliplatin and capecitabine (XELOX). Hematoxylin-eosin (HE) staining revealed that the tumor-stroma ratio (TSR) of CRC was affected by XELOX treatment. Immunohistochemistry (IHC) and senescence-associated ?-galactosidase (SA?G) staining were used to verify a stable model of senescent fibroblasts. IHC analysis showed that high expression levels of galactosylceramidase (GALC) and significant senescence-associated ?-galactosidase (SA?G) staining were associated with CRC patient survival. We observed that fibroblasts overexpressing GALC underwent cell cycle arrest. Changes in cell morphology and cell cycle characteristics were accompanied by the upregulation of the p16, p21, and p53 gene, and the downregulation of hTERT expression. In a co-culture system, fibroblasts overexpressing GALC significantly increased the proliferation of CRC cells. Transmission electron microscopy (TEM) analysis confirmed that GALC overexpression fibroblasts co-cultured with CRC caused changes in CRC cell morphology. The aging fibroblast co-culture group (70%) had a higher migration ability. In vivo experiments and transcriptomics analysis were performed to verify the effect of senescent fibroblasts on tumor formation and to identify the potential mechanisms for the above results. We found that a high expression of ATF3 was related to good survival rates. However, a high expression of KIAA0907 was bad for survival rates (p < 0.05). The knockdown of ATF3 can promote cell proliferation, migration, and clonogenic assays, while downregulation of KIAA0907 inhibits cell proliferation, migration, and clonogenic assays. The results demonstrate that senescent fibroblasts with a high level of GALC regulated several aspects of the tumor growth process, including migration and invasion.

SUBMITTER: Yang M

PROVIDER: S-EPMC7154132 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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GALC Triggers Tumorigenicity of Colorectal Cancer via Senescent Fibroblasts.

Yang Mengdi M Jiang Zhiyuan Z Yao Guangyu G Wang Zhiyu Z Sun Jing J Qin Huanlong H Zhao Hui H

Frontiers in oncology 20200407

Colorectal cancer (CRC)-associated senescent fibroblasts may play a crucial role in tumor progression, but the mechanism remains unclear. In order to solve this complicated problem, we randomly collected 16 patients with CRC, who had been treated with oxaliplatin and capecitabine (XELOX). Hematoxylin-eosin (HE) staining revealed that the tumor-stroma ratio (TSR) of CRC was affected by XELOX treatment. Immunohistochemistry (IHC) and senescence-associated β-galactosidase (SAβG) staining were used ...[more]

PMID: 32318333

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Project description:The incidence of carcinoma increases greatly with aging, but the cellular and molecular mechanisms underlying this correlation are only partly known. It is established that senescent fibroblasts promote the malignant progression of already-transformed cells through secretion of inflammatory mediators. We investigated here whether the senescent fibroblast secretome might have an impact on the very first stages of carcinogenesis. We chose the cultured normal primary human epidermal keratinocyte model, because after these cells reach the senescence plateau, cells with transformed and tumorigenic properties systematically and spontaneously emerge from the plateau. In the presence of medium conditioned by autologous senescent dermal fibroblasts, a higher frequency of post-senescence emergence was observed and the post-senescence emergent cells showed enhanced migratory properties and a more marked epithelial-mesenchymal transition. Using pharmacological inhibitors, siRNAs, and blocking antibodies, we demonstrated that the MMP-1 and MMP-2 matrix metalloproteinases, known to participate in late stages of cancer invasion and metastasis, are responsible for this enhancement of early migratory capacity. We present evidence that MMPs act by activating the protease-activated receptor 1 (PAR-1), whose expression is specifically increased in post-senescence emergent keratinocytes. The physiopathological relevance of these results was tested by analyzing MMP activity and PAR-1 expression in skin sections. Both were higher in skin sections from aged subjects than in ones from young subjects. Altogether, our results suggest that during aging, the dermal and epidermal skin compartments might be activated coordinately for initiation of skin carcinoma, via a paracrine axis in which MMPs secreted by senescent fibroblasts promote very early epithelial-mesenchymal transition of keratinocytes undergoing transformation and oversynthesizing the MMP-activatable receptor PAR-1.

Project description:Excessive exposure to ultraviolet (UV) light is known to induce photoaging in the skin, necessitating the development of effective anti-photoaging strategies to mitigate the adverse effects of UV radiation. Understanding the biofunctional characteristics of diverse skin cell types and unraveling the molecular modifications implicated in the aging process are pivotal in comprehending the intricacies of photoaging in human skin. Such insights are essential for paving the way for innovative interventions to counteract the deleterious impact of UV radiation on the skin. The single-cell RNA sequencing data of UVB-irradiated and normal control mouse skin in GSE173385 were downloaded from the Gene Expression Omniniub (GEO) database. First, cell types were identified using Seurat for normalization, dimensionality reduction and clustering. Next, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis were executed on these cell subpopulations. Using FindAllMarkers in the Seurat package to identify differential gene expression and Monocle2 cell trajectory analysis, we screened out hub genes related to the development trajectory of senescent fibroblasts during photoaging, and then combined it with 307 aging-related genes collected in the HAGR library, we finally identified two biomarkers. The efficiency of biomarkers in diagnosing UV radiation photoaging was also evaluated in the dataset. Concurrently, the immune infiltration of identified biomarkers under UV radiation has also been further explored. Moreover, we employed the Enrichr platform to conduct a comprehensive screening of drug molecules associated with the identified biomarkers. Our comprehensive analysis, employing Seurat for normalization, dimensionality reduction, and clustering, successfully identified ten distinct cell types within the samples. Then GO functional enrichment analysis showed that senescent fibroblasts are mainly involved in the regulation of immune effector processes such as cytokine-mediated signaling pathways, regulation of epithelial cell proliferation and intercellular adhesion. Afterwards, KEGG analysis determined the main biological pathways are: IL-17 signaling pathway, Cytokine-cytokine receptor interaction, Metabolism of xenobiotics by cytochrome P450. After differential gene expression and Monocle2 cell trajectory analysis, we matched the obtained hub genes with the aging-related genes collected in the HAGR library, and finally screened out two relevant biomarkers: Apoe and Gdf15 which are related to the development trajectory of senescent fibroblasts during photoaging. Meanwhile, the immune infiltration further implied that the expression of these two biomarkers was significantly correlated with immune cells. In addition, the Enrichr platform was used to screen the drug molecules related to these biomarkers. This strategic approach aimed to pinpoint effective molecular targets for the prevention and treatment of photoaging. Our investigation has effectively characterized biomarkers associated with fibroblast senescence during photoaging at the single-cell level, We have validated their correlation with cellular immune inflammation and identified potential drug targets through the utilization of the Enrichr platform. This foundational research establishes a robust basis for the development of therapeutic interventions targeting skin diseases resulting from photoaging.

Dataset Information

GALC Triggers Tumorigenicity of Colorectal Cancer via Senescent Fibroblasts.

Publications

GALC Triggers Tumorigenicity of Colorectal Cancer via Senescent Fibroblasts.

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