RESUMO
BACKGROUND: The single nucleotide polymorphism (SNP) rs1893217 within the gene locus encoding PTPN2 represents a risk factor for inflammatory bowel disease (IBD). Our previous work demonstrated reduced PTPN2 activity and subsequently increased inflammatory signaling upon presence of SNP rs1893217. The naturally occurring polyamine spermidine reduces pro-inflammatory signaling via induction of PTPN2 activity; however, the effect of SNP rs1893217 on the anti-inflammatory potential of spermidine is still unknown. Here, we investigated how presence of SNP rs1893217 affects treatment efficacy of spermidine and whether it might serve as a potential biomarker for spermidine treatment. METHODS: Human T84 (wild-type [WT] for PTPN2 SNP rs1893217) and HT29 (heterozygous for PTPN2 SNP rs1893217) intestinal epithelial cells (IECs) were treated with several polyamines from the putrescine-spermidine pathway. T84 and HT29 IECs, THP-1 monocytes (WT and transfected with a lentiviral vector expressing PTPN2 SNP rs1893217) and genotyped, patient-derived peripheral blood mononuclear cells were challenged with IFN-γ and/or spermidine. RESULTS: Among the analyzed polyamines, spermidine was the most efficient activator of PTPN2 phosphatase activity, regardless of the PTPN2 genotype. Spermidine suppressed IFN-γ-induced STAT1 and STAT3 phosphorylation, along with decreased mRNA expression of ICAM-1, NOD2, and IFNG in IECs and monocytes. Of note, these effects were clearly more pronounced when the disease-associated PTPN2 C-variant in SNP rs1893217 was present. CONCLUSIONS: Our data demonstrate that spermidine is the most potent polyamine in the putrescine-spermine axis for inducing PTPN2 enzymatic activity. The anti-inflammatory effect of spermidine is potentiated in the presence of SNP rs1893217, and this SNP might thus be a useful biomarker for possible spermidine-treatment in IBD patients.
Assuntos
Anti-Inflamatórios/metabolismo , Doenças Inflamatórias Intestinais/genética , Polimorfismo de Nucleotídeo Único/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Espermidina/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Células Epiteliais/metabolismo , Genótipo , Humanos , Doenças Inflamatórias Intestinais/sangue , Interferon gama/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Leucócitos Mononucleares/metabolismo , Fosforilação/genética , Transdução de Sinais/genéticaRESUMO
BACKGROUND/OBJECTIVES: Protein tyrosine phosphatase nonreceptor type 23 (PTPN23) has recently been associated with several human epithelial cancers via regulation of growth factor signaling. Colorectal carcinoma (CRC) is a leading cause for cancer-related death worldwide and is associated with aberrant epidermal (EGF) and vascular endothelial growth factor signaling. Here, we investigated whether PTPN23 might play a role in CRC. METHODS: Expression of PTPN23 was analyzed in CRC tissue by immunohistochemistry. PTPN23 was silenced in HT-29 cells to address the role of PTPN23 in EGF signaling, gene expression, and cell migration. RESULTS: PTPN23 silencing in HT-29 and Caco-2 intestinal epithelial cancer cells significantly enhanced activation of pro-oncogenic signaling molecules and genes promoting epithelial-to-mesenchymal transition (EMT) upon EGF treatment, while genes encoding tight junction proteins were significantly reduced. CONCLUSIONS: Our data clearly indicate that loss of PTPN23 is associated with increased activation of pro-oncogenic signaling pathways and an enhanced ability of human intestinal cancer cells to undergo EMT. Taken together, these findings show that PTPN23 acts as a tumor suppressor gene in CRC.