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http://ir.nhri.org.tw/handle/3990099045/10571
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| Title: | Intestine-specific homeobox gene ISX Integrates IL6 signaling, tryptophan catabolism, and immune suppression |
| Authors: | Wang, LT;Chiou, SS;Chai, CY;Hsi, E;Yokoyama, KK;Wang, SN;Huang, SK;Hsu, SH |
| Contributors: | National Institute of Environmental Health Sciences |
| Abstract: | The intestine-specific homeobox transcription factor ISX is an IL-6-inducible proto-oncogene implicated in the development of hepatocellular carcinoma (HCC), but its mechanistic contributions to this process are undefined. In this study, we provide evidence that ISX mediates a positive feedback loop integrating inflammation, tryptophan cataboism and immune suppression. We found that ISX mediated IL-6-induced expression of the tryptophan catabolic enzymes IDO1 and TDO2 in HCC cells, resulting in an ISX-dependent increase in the tryptophan catabolite kynurenine and its receptor aryl hydrocarbon receptor (AHR). Activation of this kynurenine/AHR signaling axis acted through a positive feedback mechanism to increase ISX expression and enhance cellular proliferation and tumorigenic potential. RNAi-mediated attenuation of ISX or AHR reversed these effects. In an IDO1-dependent manner, ectopic expression of ISX induced expression of genes encoding the critical immune modulators CD86 (B7-2) and PD-L1, through which ISX conferred a significant suppressive effect on the CD8+ T cell response. In HCC specimens, expression of IDO1, kynurenine, AHR and PD-L1 correlated negatively with survival. Overall, our results identified a feed-forward mechanism of immune suppression in HCC organized by ISX which involves kynurenine-AHR signaling and PD-L1, offering insights into immune escape by HCC which may improve its therapeutic management. |
| Date: | 2017-08 |
| Relation: | Cancer Research. 2017 Aug;77(15):4065-4077. |
| Link to: | http://dx.doi.org/10.1158/0008-5472.can-17-0090 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0008-5472&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000406677800009 |
| Cited Times(Scopus): | https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85026911335 |
| Appears in Collections: | [黃嘯谷] 期刊論文
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| PUB28625979.pdf | | 1756Kb | Adobe PDF | 321 | View/Open |
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