IL2RG, identified as overexpressed by RNA-seq profiling of pancreatic intraepithelial neoplasia, mediates pancreatic cancer growth.

Michael Ayars,Michael Borges,Koji Shindo,Michael Goggins,Haeryoung Kim,Jun Yu,Ralph H Hruban,Anne Macgregor-Das,Eileen O’Sullivan

doi:10.18632/oncotarget.19848

Michael Ayars, Michael Borges + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.19848

Copy DOI

Abstract

Pancreatic ductal adenocarcinoma evolves from precursor lesions, the most common of which is pancreatic intraepithelial neoplasia (PanIN). We performed RNA-sequencing analysis of laser capture microdissected PanINs and normal pancreatic duct cells to identify differentially expressed genes between PanINs and normal pancreatic duct, and between low-grade and high-grade PanINs. One of the most highly overexpressed transcripts identified in PanIN is interleukin-2 receptor subunit gamma (IL2RG) encoding the common gamma chain, IL2Rγ. CRISPR-mediated knockout of IL2RG in orthotopically implanted pancreatic cancer cells resulted in attenuated tumor growth in mice and reduced JAK3 expression in orthotopic tumors. These results indicate that IL2Rγ/JAK3 signaling contributes to pancreatic cancer cell growth in vivo.

Highlights

Pancreatic cancer is the third-leading cause of cancer death in the USA, with a 5-year survival rate of 8% [1]
Most pancreatic ductal adenocarcinomas are thought to arise from pancreatic intraepithelial neoplasia (PanIN) [2]
Most PanIN-3 lesions are found in association with an invasive ductal adenocarcinoma [2], but PanIN-3 lesions are identified in the absence of cancer in pancreata of highrisk patients that have undergone pancreatic resection for concerning pancreatic imaging abnormalities during pancreatic screening [7, 8]

Summary

INTRODUCTION

Pancreatic cancer is the third-leading cause of cancer death in the USA, with a 5-year survival rate of 8% [1]. PanINs are small, microscopic lesions currently only identifiable by microscopic analysis of resected pancreata. The major genetic alterations of PanINs have been identified [3, 9], few studies have characterized the transcriptional changes of PanINs [10]. Most of these studies have evaluated candidate genes identified as differential expressed in pancreatic cancer tissues. An analysis of microdissected low-grade PanIN using cDNA microarrays has found differentially expression of extrapancreatic foregut markers [10]. We performed RNAseq analysis of microdissected PanINs and normal pancreatic duct samples to identify differentially expressed transcripts. We chose to examine the function of one of the novel and most highly overexpressed transcripts in PanIN, IL2RG, a gene encoding the IL2 gamma receptor, Il2Rγ, which mediates proliferation signals through the JAK/Stat pathway

RESULTS AND DISCUSSION

MATERIALS AND METHODS

CONFLICTS OF INTEREST