Lack of interferon-γ receptor results in a microenvironment favorable for intestinal tumorigenesis

Abstract

// Caibo Zhang 1, 2 , Dong Hou 1 , Haifeng Wei 3 , Minnan Zhao 1 , Lin Yang 4 , Qiao Liu 1 , Xiyu Zhang 1 , Yaoqin Gong 1 , Changshun Shao 1, 5 1 Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China 2 Department of Life Sciences, Qilu Normal University, Jinan, Shandong, 250013, China 3 First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250012, China 4 Huaiyin People’s Hospital, Jinan, Shandong, 250021, China 5 Department of Genetics/Human Genetics Institute of New Jersey, Piscataway, NJ, 08854, USA Correspondence to: Changshun Shao, email: changshun.shao@gmail.com Keywords: IFN-γ receptor, intestinal tumorigenesis, gene expression profiling, inflammation, tumor microenvironment Received: January 13, 2016      Accepted: May 08, 2016      Published: June 07, 2016 ABSTRACT IFN-γ plays an important role in innate and adaptive immunity. IFN-γ signaling is also involved in tumorigenesis, with both pro- and antitumor activities documented. We here report the characterization of intestinal tumorigenesis in Apc Min/ + mice that lack IFN-γ receptor. We observed that Ifngr1 −/− Apc Min/+ mice are shorter-lived than Ifngr1 +/+ Apc Min/+ mice. The tumors in Ifngr1 −/− Apc Min/+ mice are more likely to progress into invasive adenocarcinomas. Gene expression profiling by RNA sequencing revealed a significant upregulation of genes involved in inflammation and tissue remodeling in tumors of Ifngr1 −/− Apc Min/+ mice when compared to those in Ifngr1 +/+ Apc Min/+ mice. In particular, five genes encoding matrix metallopeptidases (MMPs) were among the upregulated. On the other hand, genes that promote or maintain intestinal differentiation, such as Cdx2 , Cdhr2 and Cdhr5 , were downregulated. Tumor-associated macrophages were more abundant and were more favored toward M2 polarization in Ifngr1 −/− Apc Min/+ mice than in Ifngr1 +/+ Apc Min/+ mice. Furthermore, the Ifngr1 was significantly downregulated in intestinal tumors when compared to mucosa. A similar trend was noted for human colorectal carcinomas. Together, our results indicate that adequate IFN-γ signaling is critical for maintaining a tumor-prohibitive microenvironment.