miR-34a functions as a tumor suppressor modulating EGFR in glioblastoma multiforme

Abstract

Chromosome 1p36.23 is frequently deleted in glioblastoma multiforme (GBM). miR-34a localizes in this region. Our experiments found that miR-34a was often deleted and epidermal growth factor receptor (EGFR) was frequently amplified in genomic DNA of 55 GBMs using single-nucleotide polymorphism DNA microarray. Notably, we found that the mean survival time was significantly shortened for patients whose GBMs had both EGFR amplification and miR-34a deletion. Expression of miR-34a was significantly lower in GBM samples compared with normal brain tissue. Forced expression of miR-34a in GBM cells decreased their ability to migrate and profoundly decreased their levels of cyclin-A1, -B1, -D1, and -D3, as well as cyclin-dependent kinase and increased expression of cyclin kinase inhibitor proteins (p21, p27). Also, human GBM cells (U251) stable overexpressing mir-34a formed smaller tumors when growing as xenografts in immunodeficient mice compared with wild-type U251 GBM cells. Furthermore, the protein expression of EGFR decreased in the cells with forced overexpression of miR-34a. Additional studies showed that mir-34a targeted Yin Yang-1 (YY1) and YY1 is a transcription factor that can stimulate the expression of EGFR. Thus, our data suggest that miR-34a acts as a tumor suppressor by inhibiting growth of GBM cells in vitro and in vivo associated with moderating the expression of cell-cycle proteins and EGFR. Moreover, we discovered for the first time that both deletion of miR-34a and amplification of EGFR were associated with significantly decreased overall survival of GBM patients.

Yin Yang 1 is a target of microRNA-34 family and contributes to gastric carcinogenesis

“…YY1 was found to cross-talk with miRNAs at least including miR-1 [20], miR-7 [19], miR-29 [15], miR-34a [10, 17, 18], miR-190 [13, 14], and miR-206 [16]. It was speculated that this combinatorial control may more precisely tune the levels of their down-stream target genes as compared with regulation by either mechanism alone [20].…”

MIR34Aregulates autophagy and apoptosis by targetingHMGB1in the retinoblastoma cell

“…8 MIR34A has been implicated in multiple cancer types, including retinoblastoma, and its expression is a prognostic parameter. [9][10][11][12][13] Numerous studies demonstrate that MIR34A is critically involved in regulating diverse tumor cellular processes such as apoptosis and the cell cycle. 7,[14][15][16][17] Identifying functionally important mRNA targets of MIR34A is essential to unraveling its biological function and is helpful for cancer drug development.…”

Tumor stem cells from glioblastoma multiforme

“…Согласно современным представлениям количество микроРНК составляет ~1 % от генома высших эукариот и регули-рует 10-30 % генов [53][54][55][56][57][58][59][60][61][62][63].…”

“…На данный момент известно о 95 микроРНК с пони-женной и о 255 с повышенной экспрессией при мно-жественной глиобластоме [55]. В других исследова-ниях выявлены 43 аберрантных микроРНК (miR-21, miR-128, miR-326, miR-34a), экспрессирующихся в гли-омах и свя занных с пролиферацией, инвазией ОСК глиобластом [55][56][57][58][59][60][61][62][63]. Так, при гиперэкспрессии miR-128 поддерживается образование нейросфер в культуре клеток [56].…”

“…Амплифика-ция EGFR и делеция miR-34 связаны с укороченным периодом продолжительности жизни у больных мульти-формной глиобластомой [59]. Трансфекция miR-34a в ОСК приводит к снижению пролиферации и выжи-ваемости клеток, миграции, а также к уменьшению экспрессии CD133 и нестина [60,61]; miR-137 также ингибирует самообновление и дифференцировку ОСК глиобластомы через снижение уровней Oct4, Nanog и SOX2 [62].…”