Neurological Surgery 脳神経外科42巻8号

2014年08月発行

総説

神経膠腫におけるエピジェネティクス機構とnon-coding RNAs

著者： 出口彰一¹ 近藤豊² 夏目敦至¹

所属機関： ¹名古屋大学大学院医学系研究科脳神経外科 ²愛知県がんセンター研究所ゲノム制御研究部

ページ範囲：P.701 - P.709

Ⅰ．はじめに

　Glioblastoma multiforme（GBM）はgliomaの中で最も悪性度が高い．“multiforme”が示すように，この腫瘍の組織病理は非常に多岐にわたり，腫瘍内にheterogeneity（不均一性）がみられ，異なった形態や分化過程を経た腫瘍細胞の集簇である⁴⁹⁾．外科的手術，放射線治療，temozolomide（TMZ）などの化学療法を複合した治療を行っても，診断後の5年生存率は5%以下である⁵³⁾．GBMを悪性たらしめる機構を明らかにすることが，新たな治療開発の鍵である．

　GBMを含む多くの癌の共通の特徴として，genomeの変化と同時に異常なepigenomeの変化も発見されている²¹⁾．The Cancer Genome Atlas（TCGA）での大規模なprofiling studyではgliomaの発生および進展に対してより深い考察がなされている³⁸⁾．まず，注目すべき発見はepigenomeを調整している遺伝子に多数の不活化の変異が認められたことである．この変異によってDNAメチル化，ヒストン修飾やヌクレオソームの形態に変化が生じ，それが異常な遺伝子の発現につながっている⁹⁾．例えばgliomaの一部である，low grade gliomasやsecondary GBMはIDH1/2の変異とプロモーター領域にメチル化が多いG-CIMP（glioma CpG island methylator phenotype）が特徴的である．このようにgenomeとepigenomeの変化は独立した事象ではなく，お互いに関連し，クロストークされていると考えられ，それらを明らかにすることがGBMに対する新たな治療戦略への道標となる．

　タンパク質に翻訳され得る塩基配列情報をもつmessenger RNA（mRNA）はDNAから転写された遺伝情報を担っている．このmRNAと相補的に結合または，翻訳開始部位である3'末端に結合することでmRNAを破壊し，また翻訳を妨げるRNAの存在が発見され，これらをnon-coding RNAs（ncRNAs）という．特にmicroRNA（miRNA，miR）とlong non-coding RNAs（lncRNAs）などのncRNAsは多くの細胞機能と関連しているとされる²²⁾．最近の報告ではncRNAsは細胞分化や増殖の重要な調節因子としてだけでなく，多種の癌の癌抑制もしくは癌遺伝子の機能も有するといわれている¹¹⁾．つまりncRNAはgenomeに制御されない遺伝子の発現機構，epigenetics機構の1つであるといえる．このように，ncRNAsやepigenomeの制御因子は，腫瘍形成を含む多種多様の生理的，病理的な過程においてとても重要な役割を演じている．

　ncRNAを含めたepigenomeによる発現調節機構を理解することは，epigenomeを標的とした新たな治療を提示することにつながる．本稿ではgliomaにおけるepigenomeの研究についての近年の進歩を概説し，この疾患に対する新しい治療戦略の展望を示す．

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