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Mol Cell Biol. 2018 Jan 16;38(3). pii: e00427-17. doi: 10.1128/MCB.00427-17. Print 2018 Feb 1.

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

Author information

1
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA.
2
Sidney Kimmel Cancer Center at the Jefferson Pancreatic, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
3
University of Kansas Medical Center, Kansas City, Kansas, USA.
4
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA sawickij@mlhs.org.

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-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.

KEYWORDS:

HuR; cancer; inflammation; pancreas

PMID:
29133460
PMCID:
PMC5770537
DOI:
10.1128/MCB.00427-17
[Indexed for MEDLINE]
Free PMC Article

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