Retinoid acid induced 16 deficiency aggravates colitis and colitis-associated tumorigenesis in mice

Yu-Lin Xu,Cui-Ling Ding,Wen Wang,Zhong-Tian Qi,Chun-Lin Qian

doi:10.1038/s41419-019-2186-9

Yu-Lin Xu, Cui-Ling Ding + Show 3 more

Open Access

https://doi.org/10.1038/s41419-019-2186-9

Copy DOI

Journal: Cell Death & Disease	Publication Date: Dec 1, 2019
Citations: 10	License type: open-access

Affiliation: Second Military Medical University

Abstract

Inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC) is a serious health issue, but etiopathological factors remain unclear. Although some studies reported the roles of Retinoid acid induced 16 (RAI16) in the tumorigenesis of hepatocellular carcinoma and PKA signaling, the roles of RAI16 in IBD and CRC are undressed. RAI16−/− mice were generated and the roles of RAI16 were addressed in dextran sodium sulfate (DSS) or azoxymethane (AOM)-DSS induced IBD or CAC mouse models, respectively. At first, RAI16−/− mice were viable, fertile with no apparent defects. Then, it was found that RAI16−/− mice were more susceptibility to colitis induced by DSS than wild type (WT) littermates, which was evaluated by disease activity index and histological score. Furthermore, the expressions of tissues repair associated molecules Cox2, Ereg and MMP-10 were significantly decreased in RAI16−/− colon under DSS treatment. Gut barrier related genes including antimicrobial peptides Reg3b and Reg3g and intestinal mucus genes Muc4, Muc6 and Muc20 were reduced in RAI16−/− colon. These findings indicated that RAI16 may function to affect genes involved in intestinal barrier function and immunoprotective inflammation. Accordingly, RAI16−/− mice displayed significantly increased tumor burden compared with WT mice assessed in CAC model induced by AOM/DSS. Much more Ki67 + nuclei were observed in RAI16−/− tumors suggesting RAI16 to be critical in colonic cell proliferation during tumorigenesis. Conclusively, we demonstrate the roles of RAI16 in colonic inflammation and inflammation-associated tumorigenesis by using a novel RAI16−/− mouse model for the first time.

Highlights

Colitis-associated colorectal cancer (CAC) is one of the most commonly diagnosed and lethal cancer in developed countries[1,2]
IL-6, IL-1β and TNF-α, which were reported to be involved in inflammatory bowel disease (IBD) commonly, have been widely used to evaluate the severity of IBD14
IL-6, IL-1β and TNF-α mRNAs increased significantly in dextran sodium sulfate (DSS) treated wild type (WT) and Retinoid acid induced 16 (RAI16)−/− mice, there is no significance found between WT and RAI16−/− mice under DSS treatment, even IL-6 mRNA showed a bit of decrease in RAI16−/− mice compared with WT mice

Summary

Introduction

Colitis-associated colorectal cancer (CAC) is one of the most commonly diagnosed and lethal cancer in developed countries[1,2]. More evidences suggest that excessive inflammatory condition in the gastrointestinal tract pose a high risk for CAC development[3]. Patients with inflammatory bowel disease (IBD) are at a higher risk of developing CAC4. IBD is a chronic inflammatory disease of the colon characterized by mucosal inflammation[5,6]. The studies reported its role on cell proliferation and differentiation[9,10,11], the functional study on RAI16 ( called FAM160B2) is limited. Our group firstly reported that RAI16 enhanced tumorigenesis in hepatocellular carcinoma (HCC) due to the resistance to apoptosis and could serve as biomarker for HCC diagnosis[12].

Methods

Results

Conclusion