Abstract 4003: Involving of PGD2 signal pathway in the RIG1-mediated suppression of cell invasion in testis cells
Authors: Fu-Ming Tsai, Chang-Chieh Wu, Rong-Yaun Shyu, Shun-Yuan Jiang
Journal: Cancer Research (2012)

Abstract Retinoid-inducible gene 1 (RIG1), also called tazarotene induced gene 3 (TIG3), belongs to the HREV107 gene family that contains five members in humans. Proteins of the HREV107 family share four conserved domains, a proline-rich motif located at the N-terminus, followed by a conserved H-box, the NC domain and a C-terminal transmembrane domain. RIG1 is expressed in high levels in well-differentiated tissues, but the expression of RIG1 decreases in cancer tissues and cancer cell lines. RIG1 stimulates cellular differentiation of keratinocytes, which is mediated by the activation of type I tissue transglutaminase. In addition, RIG1 was shown to inhibit the RAS signal pathways in cervical and gastric cancer cells. However, the direct interactions of RIG1/Type I tissue transglutaminase or RIG1/RAS were observed in cervical cancer cells. Until now, the mechanisms of anti-cancer /induced-cellular differentiation effects caused by RIG1 induced proteins have not been reported. We have found that Prostaglandin D2 synthase (PTGDS) interacted with RIG1 by yeast two hybrid screens. Further, we found PTGDS immunoprecipitated with RIG1 in NT2/D1 testis cell lysate. We also found PTGDS co-localized with RIG1 at the endomembrane. In RIG1-transfected cell, increasing expression of PGD2 production can be observed after stimulating by PTGDS. Thus, this indicated RIG1 can enhance PTGDS activity. Otherwise, cAMP and SOX9 are targets for PGD2 signaling. Our results revealed that cAMP but not SOX9 were upregulated in RIG1-expressing NT2/D1 testis cells. Pervious study indicated that RIG1 is a phospholipid-metabolizing enzyme (PLA) which involved in the phospholipid metabolism and the PLA activity is essential for the PGD2 production. RIG1 upregulated the PGD2 and cAMP production will not be affected in PLA inhibitor AACOCF3 treated-RIG1-expressing NT2/D1 cells. Silencing of PTGDS expression significantly decreased RIG1-mediated cAMP and PGD2 production. These results suggested that RIG1-induced PGD2 production is mediated by increasing the PTGDS activity but not PLA activity of RIG1. Either cell death or cell viability was not affected in RIG1-expressing cells. However, RIG1 significantly inhibited the cell migration and invasion in NT2/D1 cells. Knockdown of PTGDS expression but not treating cells with AACOCF3 can alleviated RIG1-induced invasion and migration suppression of NT2/D1 cells. This result indicated that RIG1 will cause cell invasion suppression though the PGD2 signaling pathway. In conclusion, RIG1 can interact with PTGDS to enhance its function and further suppress the NT2/D1 cell migration and invasion. Our study suggested that RIG1-PGD2 signaling might play an important role in cell differentiation of testis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4003. doi:1538-7445.AM2012-4003