Elevated HuR in pancreas promotes a pancreatitis-like inflammatory microenvironment that facilitates tumor development

Weidan Peng, Narumi Furuuchi, Ludmila Aslanukova, Yu Hung Huang, Samantha Z. Brown, Wei Jiang, Sankar Addya, Vikalp Vishwakarma, Erika Peters, Jonathan R. Brody, Dan A. Dixon, Janet A. Sawicki

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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-ras G12D to result in a 3.4-fold increase in pancreatic ductal adenocarcinoma (PDAC) incidence compared to PDAC presence in K-ras G12D 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.

Original languageEnglish (US)
Article numbere00427-17
JournalMolecular and cellular biology
Volume38
Issue number3
DOIs
StatePublished - Feb 1 2018
Externally publishedYes

Keywords

  • Cancer
  • HuR
  • Inflammation
  • Pancreas

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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