那須 亮

マイクロRNA(miRNA)は、哺乳類では2000年にその存在が明らかになった約20塩基ほどの機能性小分子RNAである。遺伝子をコードしないゲノム領域から転写される非コードRNAの機能的な重要性は近年続々と明らかになっているが、そのなかにおいても、もっとも研究が進み、その高い生物学的な意義はすでに多くの報告によって確立された概念となっている。がん転移においてもその機能は多種多彩である。そのなかから本稿では、転移におけるエクソソーム、上皮間葉移行(EMT)によるがん転移促進、低酸素環境が制御するがん転移・骨転移における機能的なmiRNAについて、さらには脳転移巣におけるアストロサイト由来のmiR-19aによるPTEN発現抑制について、最新の知見を紹介する。(著者抄録)

Abstract Despite huge efforts, glioblastoma has remained one of the most intractable tumors. According to the cancer stem cell theory, the aggressive phenotype and poor prognosis of glioblastoma are attributed to the rare tumor cells called glioblastoma cancer stem cells (GSCs), which are poorly differentiated and share features with neural stem cells. However, the molecular mechanisms underlying the tumorigenicity and stemness of GSCs are still to be elucidated. In this study, we performed an RNA-interference (RNAi)-based screen and identified 29 genes that positively regulate the expression of CD133. Among these, we focused on the histone deacetylase SIRT2. When the function of SIRT2 was inhibited by RNAi or the specific inhibitor AGK2, sphere-forming capacity and cell proliferation were significantly decreased. In addition, knockdown of SIRT2 induced apoptosis in GSCs but not in “serum-differentiated” GSCs, suggesting a stem-cell specific function of SIRT2. Furthermore, GSCs in which SIRT2 expression was stably repressed by a specific small hairpin RNA (shRNA) showed impaired tumorigenicity when transplanted into immunocompromised mice. Taken together, these results imply that SIRT2 is a possible therapeutic target for glioblastoma and the existing SIRT2 inhibitors should be useful seed compounds for novel antitumor drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-104. doi:10.1158/1538-7445.AM2011-LB-104