Retinoic acid induced 16 deficiency exacerbates high-fat diet-induced steatohepatitis in mice.

Non-alcoholic fatty liver disease (NAFLD) associated with obesity may progress to non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma (HCC). Retinoic acid induced 16 (RAI16) plays an important role in cell apoptosis and is also a potential marker for HCC. Here we aimed to test the effect of RAI16 deficiency on liver pathology in high-fat diet (HFD) fed mice. Wild type (WT) and RAI16 knockout (RAI16-/-) C57BL/6 mice were fed with HFD or chow for up to 12 months. With consumption of HFD diet, RAI16-/- mice on HFD developed much more excess fatty liver within 4 months than WT mice on HFD. The expressions of fatty acid synthesis associated molecules Ppar-γ, Srebp-1c and Fas were further increased in RAI16-/- mice compared with WT mice on HFD. Macrophage infiltration related molecules Mcp-1 and F4/80 and pro-inflammatory factor Lcn2 were significantly increased in RAI16-/- mice compared with WT mice on HFD. Conclusively, RAI16 deficiency exacerbated HFD-induced liver injury, associated with increased inflammation. These findings indicate that RAI16 plays an important role in HFD-induced liver pathology and might be considered as a target for treatment of NAFLD. SIGNIFICANCE: 1. RAI16-/- mice on HFD developed much more excess fatty liver. 2. RAI16-/- mice showed more macrophage infiltration and proinflammation.

Identification of retinoid acid induced 16 as a novel androgen receptor target in prostate cancer cells.

BACKGROUND: Retinoid acid induced 16 (RAI16) was reported to enhance tumorigenesis in hepatocellular carcinoma (HCC). The androgen receptor (AR) is a nuclear hormone receptor that functions as a critical oncogene in several cancer progressions. However, whether RAI16 is a candidate AR target gene that may involve in prostate cancer progression was unclear. MATERIALS & METHODS: RAI16 expression was detected in prostate cancer cells with or without the AR agonist R1881 treatment by quantitative RT-PCR and Western blot. Direct AR binding to the RAI16 promoter was tested using AR chromatin immunoprecipitation (ChIP) and luciferase assay. Cell viability and colony formation assays in response to R1881 were analyzed in cells with RAI16 knockdown by specific siRNA. RESULTS: The expression of RAI16 was high in LNCaP(AI), LNCaP(AD), C4-2 expressing AR, but low in Du145 and Pc-3 cells without AR expressing. In addition, the expression of RAI16 could be induced by 10 nM R1881 treatment LNCaP(AD) and C4-2 cells, but inhibited by AR specific siRNA treatment. Furthermore, AR binds directly to ARE3 (-2003~-1982bp) of RAI16 promoter region by ChIP and luciferase assay. RAI16 knockdown inhibited the enhancement of cell viability and colony formation of AR stimulation. CONCLUSIONS: We demonstrate for the first time that RAI16 is a direct target gene of AR. RAI16 may involved in cell growth of prostate cancer cells in response to AR signaling.

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

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.