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Elevated HuR in Pancreas Promotes a pancreatitis-like Inflammatory Microenvironment that Facilitates Tumor Development

ABSTRACT: Gene expression in pancreas of 6 month-old C mice bearing Pdx1/Cre transgene having normal pancreas was compared to that of pancreas of 6 week old TC mice in which HuR protein was specifically overexpressed in the pancreas. We used microarrays to identify gene expression changes associated with HuR overexpression-induced fibro-inflammatory response in the pancreas.

ORGANISM(S): Mus musculus

PROVIDER: GSE102508 | GEO | 2017/11/27

SECONDARY ACCESSION(S): PRJNA397909

REPOSITORIES: GEO

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Elevated HuR in Pancreas Promotes a Pancreatitis-Like Inflammatory Microenvironment That Facilitates Tumor Development.

Project description:Human antigen R (ELAVL1; HuR) is perhaps the best-characterized RNA-binding protein. Through its overexpression in various tumor types, HuR promotes posttranscriptional regulation of target genes in multiple core signaling pathways associated with tumor progression. The role of HuR overexpression in pancreatic tumorigenesis is unknown and led us to explore the consequences of HuR overexpression using a novel transgenic mouse model that has a >2-fold elevation of pancreatic HuR expression. Histologically, HuR-overexpressing pancreas displays a fibroinflammatory response and other pathological features characteristic of chronic pancreatitis. This pathology is reflected in changes in the pancreatic gene expression profile due, in part, to genes whose expression changes as a consequence of direct binding of their respective mRNAs to HuR. Older mice develop pancreatic steatosis and severe glucose intolerance. Elevated HuR cooperated with mutant K-rasG12D to result in a 3.4-fold increase in pancreatic ductal adenocarcinoma (PDAC) incidence compared to PDAC presence in K-rasG12D alone. These findings implicate HuR as a facilitator of pancreatic tumorigenesis, especially in the setting of inflammation, and a novel therapeutic target for pancreatitis treatment.

| S-EPMC5770537 | biostudies-literature

Single-cell transcriptomic analysis of mouse pancreas: characteristic features of pancreatic ductal cells in chronic pancreatitis

Project description:Chronic pancreatitis (CP) is a pathogenically complex fibro-inflammatory disorder of the pancreas. Our understanding of CP pathogenesis is partly limited by the incomplete characterization of pancreatic cell types. Here, we performed single-cell RNA sequencing on 3,386 cells from the pancreas of one control mouse and mice with caerulein-induced CP. These data provides a preliminary description of the single-cell transcriptome profiles of mouse pancreata and accurately demonstrates the characteristics of pancreatic ductal cells in CP.

2022-06-30 | GSE204844 | GEO

A PDX1 cistrome and single-cell transcriptome resource of the developing pancreas

Project description:Pancreatic and duodenal homeobox 1 (PDX1) is crucial for pancreas organogenesis, yet the dynamic changes in PDX1 binding in human or mouse developing pancreas have not been examined. To address this knowledge gap, we performed PDX1 ChIP-seq and single-cell RNA-seq using fetal human pancreata. We integrated our datasets with published datasets and revealed the dynamics of PDX1 binding and potential cell-lineage-specific PDX1 bound genes in the pancreas from fetal to adult stages. We identified a core set of developmentally conserved PDX1 bound genes that reveal the broad multifaceted role of PDX1 in pancreas development. Despite the well-known, dramatic changes in PDX1 function and expression, we found that PDX1 bound genes are largely conserved from embryonic to adult stages. This points towards a dual role of PDX1 in regulating the expression of its targets at different ages, dependent on other functionally-congruent or directly-interacting partners. We also showed that PDX1 binding is largely conserved in mouse pancreas. Together, our study reveals PDX1 targets in the developing pancreas in vivo and provides an essential resource for future studies on pancreas development.

2022-04-25 | GSE201230 | GEO

Identification of Sox9/Pdx1-coregulated Genes During Pancreas Organogenesis

Project description:Sox9/Pdx1 co-regulated target genes were identified by comparing gene expression in Sox9/Pdx1-double heterozygates versus Sox9- or Pdx1- heterozygates pancreata using microarray analysis. Pdx1LacZko (herein designated Pdx1-/+) (Offield et al. 1996) and one Sox9 allele was conditionally deleted in the developing pancreas via recombination of a Sox9-flox allele (Kist et al., 2002) using the Foxa3-Cre transgene (Lee et al., 2005). Total RNA was isolated and pooled from dorsal pancreatic epithelia of e12.5 Sox9fl/+; Foxa3-Cre (Sox9 het), Pdx1-/+ (Pdx1 het) versus Sox9fl/+; Foxa3-Cre; Pdx1-/+ (Sox9/Pdx1 double hets) littermates for three biological replicates

2015-08-07 | E-GEOD-62023 | biostudies-arrayexpress

RB Dysfunction in Pancreatic Cancer Enables TGF-beta to Promote Proliferation

Project description:Pooled KRC (LSL-KrasG12D; Rb1L/L; Pdx1-Cre: oncogenic Kras and deleted Rb1 in the pancreas) cells derived from 2 month old mice were compared to pooled KC (LSL-KrasG12D; Pdx1-Cre: oncogenic Kras in the pancreas) cells derived from 8 month old mice.

2014-02-09 | E-MEXP-3988 | biostudies-arrayexpress

RNA-seq of Pdx1-GFP+ sorted E10.5, wildtype and Hes1-/-. Neurog3-dependent Pancreas Dysgenesis Causes Ectopic Pancreas in Hes1 Mutants

Project description:RNA-seq of FACS Sorted E10.5 Pdx1-GFP+ of genotypes wildtype and Hes1-/-. Summary statement The developmental mechanisms that cause ectopic pancreas are poorly understood. We show that aberrant dorsal pancreas morphogenesis in Hes1 mutants leads to ectopic pancreas depending on the pro-endocrine gene Neurog3. Abstract Mutations in Hes1, a target gene of the Notch signalling pathway, lead to ectopic pancreas by a poorly described mechanism. Here we use genetic inactivation of Hes1 combined with lineage tracing in mouse embryos to reveal an endodermal requirement for Hes1 and that most ectopic pancreas tissue is derived from the E8.5 dorsal pancreas primordium. RNA-seq data from sorted E10.5 Pdx1-GFP+ cells from Hes1+/+ and Hes1−/− suggested that upregulation of endocrine lineage genes in Hes1−/− embryos was the major defect in the endoderm and accordingly early pancreas morphogenesis was normalised and the ectopic pancreas phenotype suppressed in Hes1−/−Neurog3−/− embryos. Analysis of other Notch pathway mutants uncovered a total depletion of progenitors in Mib1 deficient dorsal anlage, which was replaced by an anterior Gcg+ extension. Together, our results demonstrate that aberrant morphogenesis is the cause of ectopic pancreas and that a part of the endocrine differentiation program is mechanistically involved in the dysgenesis. Our results suggest that the ratio of endocrine lineage to progenitor cells is important for morphogenesis and that a strong endocrinogenic phenotype without complete progenitor depletion as seen in Hes1 mutants provokes an extreme dysgenesis that causes ectopic pancreas.

2018-08-20 | E-MTAB-6890 | biostudies-arrayexpress

Proteomic analysis of acute pancreatitis in TRP14-KO miceProteomic analysis of acute pancreatitis in TRP14-KO mice

Project description:We have studied pancreas samples in pancreas from a mouse model of acute pancreatitis, comparing wild-type animals and TRP14 KO animals. Samples are extracted with N-ethylmaleimide to block reduced cysteines, and no reducing agent is used, with a search including cysteinylated peptides. Acute pancreatitis was induced in 12 weeks-old mice (wild-type and KO for TRP14) by seven intraperitoneal injections of cerulein (50 µg/kg body weight) at 1 h intervals. Then, 1 h after the last injection, animals were euthanized under anesthesia with 3% isoflurane, exsanguinated, and the pancreas was immediately removed and processed.

2024-05-15 | PXD050765 | Pride

TrxG complex catalytic and non-catalytic activity play distinct roles in pancreas progenitor specification and differentiation (E18.5 Dpy30∆P pancreas)

Project description:Purpose: To gain insight into why Dpy30∆P acinar cells fail to express terminal makers, we performed RNA-seq using E18.5 control and Dpy30∆P pancreata. Methods: Floxed Dpy30 mice were crossed to Pdx1-Cre driver mice to obtain conditional deletion of Dpy30 exon 4 in the pancreas. In all studies, knockout mice (Dpy30∆P, Pdx1-Cre; Dpy30flox/flox) were compared to littermate controls (Dpy30flox/flox or Dpy30flox/wt). Results: Differential gene expression analysis demonstrated that endocrine cell hormones such as Ins2 and acinar cell digestive enzymes were downregulated in the E18.5 Dpy30∆P pancreas compared to controls. GO term analysis indicated that genes involved in pancreatic secretion, digestion and proteolysis were reduced in Dpy30∆P cells. Notably, transcripts with very high expression levels (above 9000 FPKM) were more downregulated in the E18.5 Dpy30∆P pancreas compared to transcripts with lower expression levels. Conclusions: Overall, these data suggest increased variation in acinar cell transcript expression in the Dpy30∆P pancreas.

2019-07-12 | GSE134180 | GEO

Identification of Sox9-Regulated Pathways During Early Pancreas Organogenesis

Project description:Sox9 target genes were identified by comparing gene expression in Sox9-ablated versus wild-type pancreata using microarray analysis. Sox9 was conditionally ablated in the developing pancreas via recombination of a Sox9-flox allele (Kist et al., 2002) using the Pdx1-Cre transgene (Gu et al., 2002). Total RNA was isolated and pooled from dorsal pancreatic epithelia of e12.5 Sox9fl/fl; Pdx1-Cre (mutant) versus Sox9fl/fl (wild-type) littermates for three biological replicates.

2012-08-01 | E-GEOD-28669 | biostudies-arrayexpress

RNA-seq of Sting overexpressing orthotopic pancreas tumors

Project description:Murine pancreatic PKCY tumor cells (p53fl/+;KrasLSL-G12D/+;Pdx1-Cre;Rosa26LSL-YFP) were engineered to overexpress Sting or empty vector control. Tumor cells were orthotopically transplanted into the pancreas of syngeneic littermates. Tumors were harvested and RNA seq for transcriptomic differences was performed.

2021-09-06 | E-MTAB-10722 | biostudies-arrayexpress

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