mRNAの安定化機構を応用した新しい腫瘍溶解アデノウイルスの開発と解析

腫瘍溶解ウイルス

北海道歯学会

北海道歯学雑誌

mRNAs containing AU-rich elements (AREs) are exported from the nucleus and stabilized in the cytoplasm of many cells, including cancer cells. AREs are RNA elements that promote the degradation of mRNA transcribed from genes associated with cell proliferation, and ARE mRNA degradat ion and stabilization are controlled by proteins that bind to AREs. HuR, a member of the embryonic lethal abnormal vision family of RNA-binding proteins, is one such protein that contributes to the nuclear export and stabilization of ARE -mRNA. Cancer cells with stabilized ARE mRNA have increased expression levels of HuR in the cytoplasm. We developed an oncolytic adenovirus (AdARET) that incorporates an ARE from the tumor necrosis factor (TNF-α) into the 3”untranslated region of the adenovirus early region 1A gene (E1A), which is essential for adenovirus replication. In cancer cells infected with AdARET, E1A mRNA containing ARE is stabilized, and the virus proliferates specifically in cancer cells. Here, we investigated the oncolytic effect of the virus and factors that enhance this effect.　AdARET infection induced the expression of E1A protein, which is essential for adenovirus proliferation, specifically in cancer cells, but E1A was hardly expressed in normal cells. Moreover, enhanced virus production was observed in infected cancer cells, A549 cells, and HeLa cells compared with non-infe cted cells. AdARET showed a concentration-dependent tumor lytic effect on cancer cells, while the combined use of A dARET and TNF-α further reduced cell viability, suggesting that TNF-α enhances the tumor lytic effect of AdARET. These results indicate that AdARET exerts tumor lytic effects specifically on cancer cells, and that these are enhanced by surrounding inflammatory molecules such as TNF-α.