Quintavalle Cristina, Mangani Davide, Roscigno Giuseppina, Romano Giulia, Diaz-Lagares Angel, Iaboni Margherita, Donnarumma Elvira, Fiore Danilo, De Marinis Pasqualino, Soini Ylermi, Esteller Manel, Condorelli Gerolama
Department of Molecular Medicine and Medical Biotechnology, "Federico II" University ofNaples, Naples, Italy ; IEOS, CNR, Naples, Italy.
PLoS One. 2013 Sep 19;8(9):e74466. doi: 10.1371/journal.pone.0074466. eCollection 2013.
Glioblastoma multiforme (GBM) is one of the most deadly types of cancer. To date, the best clinical approach for treatment is based on administration of temozolomide (TMZ) in combination with radiotherapy. Much evidence suggests that the intracellular level of the alkylating enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) impacts response to TMZ in GBM patients. MGMT expression is regulated by the methylation of its promoter. However, evidence indicates that this is not the only regulatory mechanism present. Here, we describe a hitherto unknown microRNA-mediated mechanism of MGMT expression regulation. We show that miR-221 and miR-222 are upregulated in GMB patients and that these paralogues target MGMT mRNA, inducing greater TMZ-mediated cell death. However, miR-221/miR-222 also increase DNA damage and, thus, chromosomal rearrangements. Indeed, miR-221 overexpression in glioma cells led to an increase in markers of DNA damage, an effect rescued by re-expression of MGMT. Thus, chronic miR-221/222-mediated MGMT downregulation may render cells unable to repair genetic damage. This, associated also to miR-221/222 oncogenic potential, may poor GBM prognosis.
多形性胶质母细胞瘤（GBM）是最致命的癌症类型之一。迄今为止，最佳的临床治疗方法是基于替莫唑胺（TMZ）与放射治疗联合使用。许多证据表明，烷基化酶O(6)-甲基鸟嘌呤-DNA甲基转移酶（MGMT）的细胞内水平会影响GBM患者对TMZ的反应。MGMT的表达受其启动子甲基化的调节。然而，有证据表明这并非唯一存在的调节机制。在此，我们描述了一种迄今为止未知的由微小RNA介导的MGMT表达调控机制。我们发现，miR-221和miR-222在GBM患者中上调，且这些旁系同源物靶向MGMT mRNA，导致TMZ介导的细胞死亡增加。然而，miR-221/miR-222也会增加DNA损伤，进而导致染色体重排。实际上，在胶质瘤细胞中过表达miR-221会导致DNA损伤标志物增加，而MGMT的重新表达可挽救这一效应。因此，慢性miR-221/222介导的MGMT下调可能使细胞无法修复遗传损伤。这一点，再加上miR-221/222的致癌潜力，可能会导致GBM预后不良。
