Dataset Information

Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis.

ABSTRACT: Solute carrier family 7 member 2 (SLC7A2, also known as CAT2) is an inducible transporter of the semi-essential amino acid L-arginine (L-Arg), which has been implicated in wound repair. We have reported that both SLC7A2 expression and L-Arg availability are decreased in colonic tissues from inflammatory bowel disease patients and that mice lacking Slc7a2 exhibit a more severe disease course when exposed to dextran sulfate sodium (DSS) compared to wild-type (WT) mice. Here, we present evidence that SLC7A2 plays a role in modulating colon tumorigenesis in the azoxymethane (AOM)-DSS model of colitis-associated carcinogenesis (CAC). SLC7A2 was localized predominantly to colonic epithelial cells in WT mice. Utilizing the AOM-DSS model, Slc7a2-/- mice had significantly increased tumor number, burden, and risk of high-grade dysplasia vs. WT mice. Tumors from Slc7a2-/- mice exhibited significantly increased levels of the proinflammatory cytokines/chemokines IL-1?, CXCL1, CXCL5, IL-3, CXCL2, CCL3, and CCL4, but decreased levels of IL-4, CXCL9, and CXCL10 compared to tumors from WT mice. This was accompanied by a shift toward pro-tumorigenic M2 macrophage activation in Slc7a2-deficient mice, as marked by increased colonic CD11b+F4/80+ARG1+ cells with no alteration in CD11b+F4/80+NOS2+ cells by flow cytometry and immunofluorescence microscopy. The shift toward M2 macrophage activation was confirmed in bone marrow-derived macrophages from Slc7a2-/- mice. In bone marrow chimeras between Slc7a2-/- and WT mice, the recipient genotype drove the CAC phenotype, suggesting the importance of epithelial SLC7A2 in abrogating neoplastic risk. These data reveal that SLC7A2 has a significant role in the protection from CAC in the setting of chronic colitis, and suggest that the decreased SLC7A2 in inflammatory bowel disease (IBD) may contribute to CAC risk. Strategies to enhance L-Arg availability by supplementing L-Arg and/or increasing L-Arg uptake could represent a therapeutic approach in IBD to reduce the substantial long-term risk of colorectal carcinoma.

SUBMITTER: Coburn LA

PROVIDER: S-EPMC6377304 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis.

Coburn Lori A LA Singh Kshipra K Asim Mohammad M Barry Daniel P DP Allaman Margaret M MM Al-Greene Nicole T NT Hardbower Dana M DM Polosukhina Dina D Williams Christopher S CS Delgado Alberto G AG Piazuelo M Blanca MB Washington M Kay MK Gobert Alain P AP Wilson Keith T KT

Oncogene 20180910 7

Solute carrier family 7 member 2 (SLC7A2, also known as CAT2) is an inducible transporter of the semi-essential amino acid L-arginine (L-Arg), which has been implicated in wound repair. We have reported that both SLC7A2 expression and L-Arg availability are decreased in colonic tissues from inflammatory bowel disease patients and that mice lacking Slc7a2 exhibit a more severe disease course when exposed to dextran sulfate sodium (DSS) compared to wild-type (WT) mice. Here, we present evidence th ...[more]

PMID: 30202097

Similar Datasets

Project description:Solute carrier family 25 (SLC25) encodes transport proteins at the inner mitochondrial membrane and functions as carriers for metabolites. Although SLC25 genetic variants correlate with human metabolic diseases, their roles in colon cancer remain unknown. Cases of colon cancer were retrieved from The Cancer Genome Atlas, and the transcriptionally differentially expressed members (DEMs) of SLC25 were identified. DNA level alterations, clinicopathological characteristics, and clinical survival were also investigated. A risk score model based on the DEMs was constructed to further evaluate their prognostic values in a clinical setting. The results were preliminarily validated using bioinformatic analysis of datasets from the Gene Expression Omnibus, immunohistochemical evaluations in clinical specimens, and functional experiments in colon cancer-derived cell lines. Thirty-seven DEMs were identified among 53 members of SLC25. Eight of 37 DEMs were introduced into a risk score model using integrated LASSO regression and multivariate Cox regression. Validated by GSE395282 and GSE175356, DEMs with high-risk scores were associated with the phenotypes of increasing tumor immune infiltration and decreasing glycolysis and apoptosis contents. SLC25A5 was downregulated in cancer, and its upregulation was related to better overall survival in patients from public datasets and in clinical cases. High SLC25A5 expression was an independent prognostic factor for 79 patients after surgical treatment. A negative correlation between CD8 and SLC25A5 was determined in specimens from 106 patients with advanced colon cancer. SLC25A5 attenuated cell proliferation, upregulated the expression of programmed cell death-related signatures, and exerted its biological function by inhibiting the MAPK signaling pathway. Our study reveals that mitochondrial SLC25 has prognostic value in patients with colon cancer. The bioinformatic analyses by following verification in situ and in vitro provide direction for further functional and mechanistic studies on the identified member of SLC25.

Project description:Aim: To identify potential key candidate genes, whose expression and clinical significance was further assessed in colorectal cancer (CRC). Methods: Three original microarray datasets (GSE41328, GSE22598, and GSE23878) from NCBI-GEO were used to analyze differentially expressed genes (DEGs) in CRC. Online database analyses through Oncomine and GEIPA were performed to evaluate SLC4A4 expression and explore the prognostic merit of SLC4A4 expression, which was further confirmed by analyses from QPCR based cDNA array and IHC based tissue microarray (TMA). STRING website was used to explore the interaction between SLC4A4 with other DEGs based on the protein-protein interaction (PPI) networks. Results: Analysis of three original microarray datasets from GEO identified 82 shared, differentially expressed genes (28 upregulated and 54 down-regulated) in CRC tissues. Online analyses from Oncomine and GEIPA revealed lower SLC4A4 mRNA expression in CRC tissues compared to adjacent normal tissues, which were further confirmed by QPCR based cDNA array and IHC based TMA analyses on both mRNA and protein levels. Survival analyses through GEIPA and from TMA demonstrated that low SLC4A4 expression is correlated with worse overall survival among patients with CRC. Survival analysis from Kaplan-meier plotter demonstrated that low SLC4A4 expression is significantly associated with poor progression (including relapse-free survival, overall survival, distant metastasis-free survival, post-progression survival) of patients with breast cancer, lung cancer, gastric cancer, and ovarian cancer. PPI analysis found that SLC4A4 is highly correlated with various genes, including SLC9A3, SLC26A6, ENSG00000214921, SLC26A4, SLC9A3R1, and SLC9A1. Conclusion: The mRNA and protein levels of SLC4A4 were decreased in CRC tissues, and low expression of SLC4A4 significantly correlated with shorter survival of CRC patients and poorer progression of patients with breast cancer, lung cancer, gastric cancer and ovarian cancer, suggesting potential role of SLC4A4 on tumor suppression and prognostic prediction in multiple malignancies including CRC.

Dataset Information

Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis.

Publications

Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets