Dataset Information

Visualization of epithelial-mesenchymal transition in an inflammatory microenvironment-colorectal cancer network.

ABSTRACT: Epithelial-mesenchymal transition (EMT) is a biological process by which epithelial cells acquire mesenchymal characteristics. In malignant tumors, EMT is crucial for acquisition of a mesenchymal phenotype with invasive and metastatic properties, leading to tumor progression. An inflammatory microenvironment is thought to be responsible for the development and progression of colorectal cancer (CRC); however, the precise role of inflammatory microenvironments in EMT-related CRC progression remains unclear. Here, we show the spatiotemporal visualization of CRC cells undergoing EMT using a fluorescence-guided EMT imaging system in which the mesenchymal vimentin promoter drives red fluorescent protein (RFP) expression. An inflammatory microenvironment including TNF-α, IL-1β, and cytokine-secreting inflammatory macrophages induced RFP expression in association with the EMT phenotype in CRC cells. In vivo experiments further demonstrated the distribution of RFP-positive CRC cells in rectal and metastatic tumors. Our data suggest that the EMT imaging system described here is a powerful tool for monitoring EMT in inflammatory microenvironment-CRC networks.

SUBMITTER: Ieda T

PROVIDER: S-EPMC6841984 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Visualization of epithelial-mesenchymal transition in an inflammatory microenvironment-colorectal cancer network.

Ieda Takeshi T Tazawa Hiroshi H Okabayashi Hiroki H Yano Shuya S Shigeyasu Kunitoshi K Kuroda Shinji S Ohara Toshiaki T Noma Kazuhiro K Kishimoto Hiroyuki H Nishizaki Masahiko M Kagawa Shunsuke S Shirakawa Yasuhiro Y Saitou Takashi T Imamura Takeshi T Fujiwara Toshiyoshi T

Scientific reports 20191108 1

Epithelial-mesenchymal transition (EMT) is a biological process by which epithelial cells acquire mesenchymal characteristics. In malignant tumors, EMT is crucial for acquisition of a mesenchymal phenotype with invasive and metastatic properties, leading to tumor progression. An inflammatory microenvironment is thought to be responsible for the development and progression of colorectal cancer (CRC); however, the precise role of inflammatory microenvironments in EMT-related CRC progression remain ...[more]

PMID: 31705021

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Project description:Background: An increasing number of studies have shown that Isthmin 1 (ISM1), a secreted protein, is important in tumorigenesis and invasion, including in colorectal cancer (CRC). However, the mechanisms are still unclear. This study aims to explore the function and prognosis capacity of ISM1 in CRC. Methods: We investigated the expression of ISM1 in 18 CRC tissues vs. adjacent normal tissues from GSE50760, 473 CRC tissues vs. 41 normal tissues from The Cancer Genome Atlas (TCGA), and across gastrointestinal cancer types. Differences were further confirmed in CRC tissues via quantitative real-time polymerase chain reaction (qRT-PCR). Then, we analyzed correlations between clinicopathologic features and ISM1 expression, including prognostic prediction value, using the Kaplan-Meier method and multivariate Cox regression. Gene set enrichment analysis (GSEA) was performed to identify ISM1-related pathways. In vitro experiments were performed to verify the role of ISM1 in epithelial-mesenchymal transition (EMT) and CRC progression. Results: Multiple datasets showed that ISM1 is upregulated in CRC tissues, which was validated. Patients with higher ISM1 expression had shorter overall survival (OS), and ISM1 expression served as an independent prognostic factor. Enrichment analysis showed that ISM1 upregulation was positively correlated with cancer-related pathways, such as EMT, hypoxia, and the Notch and KRAS signaling pathways. We were exclusively interested in the connection between ISM1 and EMT because 71% of genes in this pathway were significantly positively co-expressed with ISM1, which may account for why patients with higher ISM1 expression are prone to regional lymph node involvement and progression to advanced stages. In addition, we found that ISM1 was positively correlated with multiple immunosuppressive pathways such as IL2/STAT5, TNF-α/NF-κB, and TGF-β, and immune checkpoints, including PD-L1, PD-1, CTLA-4, and LAG3, which may account for upregulation of ISM1 in immunotherapy-resistant patients. Notably, through in vitro experiments, we found that ISM1 promoted EMT and colon cancer cell migration and proliferation. Conclusion: ISM1 is critical for CRC development and progression, which enhances our understanding of the low response rate of CRC to immunotherapy via immunosuppressive signaling pathways.

Project description:Protein inhibitor of activated signal transducer and activator of transcription-1 (PIAS1) is an important regulator of the inflammatory signaling network, the expression of which was decreased in gastric cancer and implicated in the development of cancer. However, its mechanism has not been elucidated. The aim of the present study was to investigate the effect of PIAS1 on epithelial-mesenchymal transition (EMT) of gastric cancer cells within the inflammatory microenvironment. Recombinant adenovirus Ad5/F35-PIASl and Ad5/F35-null plasmids were constructed to transfect SGC7901 cells. Subsequently, these plasmids were confirmed by reverse transcription polymerase chain reaction and western blotting. The cells were treated with IL-6 or Ad5/F35-PIASl+IL-6, and the control cells were treated with Ad5/F35-null+IL-6. The morphological changes to the cells were observed using inverted microscopy. The effect of PIAS1 on cell migration and invasion was evaluated by scratch wound healing and Transwell chamber assays, and the protein expression of EMT markers and phosphatidylinositol 3-kinase (PI3K)/serine/threonine-protein kinase (Akt)/matrix metalloproteinase (MMP)-9 signaling pathway was examined by western blotting. Transfection with Ad5/F35-PIASl markedly increased the PIAS1 expression in SGC7901 cells. The cells acquired the more typical spindle-shape phenotype of mesenchymal cells following co-culture with IL-6; the cells co-cultured with IL-6 and Ad5/F35-PIASl acquired changes concordant with an epithelial phenotype. The overexpression of PIAS1 significantly decreased the migratory and invasive capacities of the SGC7901 cells (P<0.01). Western blotting indicated that the expression levels of E-cadherin protein in the cells treated with Ad5/F35-PIASl+IL-6 were increased significantly and the expression levels of zinc finger protein SNAI, Twist-related protein 1, vimentin and MMP-9, and the activation of PI3K/Akt proteins were decreased when compared with IL-6- or Ad5/F35-null+IL-6-treated cells (both P<0.01). PIAS1 may inhibit EMT in gastric cancer cells within the inflammatory microenvironment via the regulation of PI3K/Akt pathway activation, and may serve an important role in the inhibition of tumor invasion and metastasis with in this microenvironment.

Dataset Information

Visualization of epithelial-mesenchymal transition in an inflammatory microenvironment-colorectal cancer network.

Publications

Visualization of epithelial-mesenchymal transition in an inflammatory microenvironment-colorectal cancer network.

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