IL22RA1/STAT3 Signaling Promotes Stemness and Tumorigenicity in Pancreatic Cancer

Weizhi He; Jinghua Wu; Juanjuan Shi; Yan-Miao Huo; Wentao Dai; Jing Geng; Ping Lu; Min-Wei Yang; Yuan Fang; Wei Wang; Zhi-Gang Zhang; Aida Habtezion; Yong-Wei Sun; Jing Xue

doi:10.1158/0008-5472.CAN-17-3131

IL22RA1/STAT3 Signaling Promotes Stemness and Tumorigenicity in Pancreatic Cancer

Cancer Res. 2018 Jun 15;78(12):3293-3305. doi: 10.1158/0008-5472.CAN-17-3131. Epub 2018 Mar 23.

Authors

Weizhi He¹, Jinghua Wu¹, Juanjuan Shi¹, Yan-Miao Huo², Wentao Dai³, Jing Geng¹, Ping Lu¹, Min-Wei Yang², Yuan Fang⁴, Wei Wang⁴, Zhi-Gang Zhang⁵, Aida Habtezion⁶, Yong-Wei Sun⁷, Jing Xue⁸

Affiliations

¹ State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ Shanghai Center for Bioinformation Technology & Shanghai Engineering Research Center of Pharmaceutical Translation, Shanghai, China.
⁴ Department of General Surgery & Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁵ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China.
⁶ Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California. jingxue@sjtu.edu.cn syw0616@126.com aidah@stanford.edu.
⁷ Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. jingxue@sjtu.edu.cn syw0616@126.com aidah@stanford.edu.
⁸ State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. jingxue@sjtu.edu.cn syw0616@126.com aidah@stanford.edu.

PMID: 29572224
DOI: 10.1158/0008-5472.CAN-17-3131

Abstract

Chronic inflammation is a feature of pancreatic cancer, but little is known about how immune cells or immune cell-related signals affect pancreatic cancer stemness and development. Our previous work showed that IL22/IL22RA1 plays a vital role in acute and chronic pancreatitis progression by mediating cross-talk between immune cells and acinar cells or stellate cells, respectively. Here, we find IL22RA1 is highly but heterogeneously expressed in pancreatic cancer cells, with high expression associated with poor prognosis of patients with pancreatic cancer. The IL22RA1^hi population from pancreatic cancer harbored higher stemness potential and tumorigenicity. Notably, IL22 promoted pancreatic cancer stemness via IL22RA1/STAT3 signaling, establishing the mechanism of regulation of cancer stemness by microenvironmental factors. Moreover, STAT3 was indispensable for the maintenance of IL22RA1^hi cells. Overall, these findings provide a therapeutic strategy for patients with PDAC with high expression of IL22RA1.Significance: IL22RA1/STAT3 signaling enhances stemness and tumorigenicity in pancreatic cancer. Cancer Res; 78(12); 3293-305. ©2018 AACR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Animals
Carcinogenesis
Carcinoma, Pancreatic Ductal / mortality
Carcinoma, Pancreatic Ductal / pathology*
Cell Self Renewal
Female
Gene Expression Regulation, Neoplastic
Humans
Interleukin-22
Interleukins / metabolism*
Male
Mice
Mice, Nude
Middle Aged
Neoplastic Stem Cells / pathology*
Pancreas / pathology
Pancreatic Neoplasms / mortality
Pancreatic Neoplasms / pathology*
Primary Cell Culture
Prognosis
Receptors, Interleukin / metabolism*
STAT3 Transcription Factor / metabolism*
Signal Transduction
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

Interleukins
Receptors, Interleukin
STAT3 Transcription Factor
STAT3 protein, human
interleukin-22 receptor