Lack of interferon-γ receptor results in a microenvironment favorable for intestinal tumorigenesis.
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 ApcMin/+ mice that lack IFN-γ receptor. We observed that Ifngr1-/-ApcMin/+ mice are shorter-lived than Ifngr1+/+ApcMin/+ mice. The tumors in Ifngr1-/-ApcMin/+ 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-/-ApcMin/+ mice when compared to those in Ifngr1+/+ApcMin/+ 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-/-ApcMin/+ mice than in Ifngr1+/+ApcMin/+ 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.
Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.|Department of Life Sciences, Qilu Normal University, Jinan, Shandong, 250013, China.
Caibo
C
Zhang
Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
Dong
D
Hou
First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250012, China.
Haifeng
H
Wei
Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
Minnan
M
Zhao
Huaiyin People's Hospital, Jinan, Shandong, 250021, China.
Lin
L
Yang
Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
Qiao
Q
Liu
Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
Xiyu
X
Zhang
Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
Yaoqin
Y
Gong
Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.|Department of Genetics/Human Genetics Institute of New Jersey, Piscataway, NJ, 08854, USA.
Changshun
C
Shao
D000818:Animals; D063646:Carcinogenesis; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018450:Disease Progression; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006706:Homeostasis; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation; D017471:Receptors, Interferon / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D059016:Tumor Microenvironment; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D020782:Matrix Metalloproteinases; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor
IFN-γ receptor; gene expression profiling; inflammation; intestinal tumorigenesis; tumor microenvironment