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Roquin-deficient T cells drive pancreatitis and tumorigenesis through IL-17 and Th17-inappropriate Cytokine production

ABSTRACT: Pancreatitis can trigger pancreatic ductal adenocarcinoma (PDAC), however, the underlying origins can be diverse and cellular and molecular mechanisms remain elusive. We show that combined genetic inactivation of the RNA-binding proteins Roquin-1 and Roquin-2 in T cells induced pancreatitis, pancreatic neoplasia and accelerated PDAC formation, if KrasG12D was expressed in acinar cells. In the pancreas, Roquin-deficient T cells were highly activated, recruited proinflammatory neutrophils via IL-17A secretion, and inappropriately produced G-CSF that, in a feed-forward loop, further induced and mobilized neutrophils. Consistently, neutralization of IL-17 or G-CSF ameliorated pancreas pathology. Roquin repressed G-CSF in two ways. It directly inhibited CSF3 mRNA expression through its 3'-UTR, and indirectly, because Roquin loss-of-function imposed transcriptional reprogramming by NF-kB and established an active enhancer at the Csf3 locus in Th17 cells. Together, we identified critical cellular and humoral components and epigenetic, transcriptional and post-transcriptional mechanisms within a regulatory circuit that prevents pancreatic cancer formation.

ORGANISM(S): Mus musculus

PROVIDER: GSE248106 | GEO | 2025/11/30

REPOSITORIES: GEO

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Project description:BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is usually incurable. Contrary to genetic mechanisms involved in PDAC pathogenesis, epigenetic alterations are ill defined. Here we determine the contribution of epigenetically silenced genes to the development of PDAC. METHODS: We investigated methylated DNAs from PDACs, chronic pancreatitis and normal pancreatic tissues using Methyl-CpG immunoprecipitation followed by microarray hybridization. Promoter methylation of selected genes was confirmed with the Epityper assay. Expression levels were evaluated by quantitative RT-PCR. WNK2 was further investigated in tissue microarrays, methylation analysis of early pancreatic intraepithelial neoplasia (PanINs), mouse models for PDAC and pancreatitis, re-expression studies after demethylation, and cell growth assays using WNK2 overexpression. RESULTS: A total of 3.8% of 27.800 interrogated CpG islands were hypermethylated in PDAC versus normal and chronic pancreatitis tissues. Hypermethylation was confirmed in 12 out of 13 selected islands and was associated with gene silencing in 4 of them. The most prominently hypermethylated gene, WNK2, was further investigated. Demethylation assays confirmed the link between methylation and expression. WNK2 hypermethylation was higher in pancreatic tumor cells than in surrounding inflamed tissues and was observed in PanIN lesions as well as in a PDAC mouse model. WNK2 mRNA and protein expression were lower in PDAC and chronic pancreatitis compared to normal tissues both in patients and mouse models. Overexpression of WNK2 led to a reduced cell growth and WNK2 expression in tissues correlated negatively with the expression of pERK1/2, a downstream target of WNK2 responsible for cell proliferation. CONCLUSIONS: WNK2 is downregulated by promoter hypermethylation early in PDAC pathogenesis and may support tumor cell growth via the ERK-MAPK pathway. 3 types of pancreatic tissue samples: 5 normals, 2 chronic pancreatitis, 7 tumors (PDAC)

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Roquin-deficient T cells drive pancreatitis and tumorigenesis through IL-17 and Th17-inappropriate Cytokine production

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