Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil.
Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil.
Int J Oncol. 2017 Dec;51(6):1929-1940. doi: 10.3892/ijo.2017.4151. Epub 2017 Oct 10.
Medulloblastoma (MB) is a malignant childhood brain tumor which at molecular level is classified into at least four major subtypes: WNT, SHH, group C and group D differing in response to treatment. Previous studies have associated changes in expression levels and activation of certain HOX genes with MB development. In the present study, we investigate the role of HOX genes in two attributes acquired by tumor cells: migration and proliferation potential, as well as, in vivo tumorigenic potential. We analyzed UW402, UW473, DAOY and ONS-76 human pediatric MB cell lines and cerebellum primary cultures. Two-color microarray-based gene expression analysis was used to identify differentially expressed HOX genes. Among the various HOX genes significantly overexpressed in DAOY and ONS-76 cell lines compared to UW402 and UW473 cell lines, HOXA10 and HOXB4 were selected for further analysis. The expression levels of these HOX genes were validated by real-time PCR. A mouse model was used to study the effect of the HOXA10 and HOXB4 genes on the in vivo tumorigenic potential and the in vitro proliferative and migration potential of MB cell lines. Our results show that the inhibition of HOXA10 in DAOY cell line led to increased in vitro cell migration while in vitro cell proliferation or in vivo tumorigenic potential were unaffected. We also observed that induced expression of HOXB4 in the UW473 cell line significantly reduced in vitro cell proliferation and migration capability of UW473 cells with no effect on the in vivo tumorigenicity. This suggests that HOXA10 plays a role in migration events and the HOXB4 gene is involved in proliferation and migration processes of medulloblastoma cells, however, it appears that these genes are not essential for the tumorigenic process of these cells.
髓母细胞瘤（MB）是一种恶性儿童脑肿瘤，在分子水平上至少可分为 4 种主要亚型：WNT、SHH、C 组和 D 组，它们对治疗的反应不同。先前的研究表明，某些 HOX 基因表达水平的变化和激活与 MB 的发生有关。在本研究中，我们研究了 HOX 基因在肿瘤细胞获得的两种特性中的作用：迁移和增殖潜能，以及体内致瘤潜能。我们分析了 UW402、UW473、DAOY 和 ONS-76 人小儿 MB 细胞系和小脑原代培养物。使用双色基于微阵列的基因表达分析来鉴定差异表达的 HOX 基因。在与 UW402 和 UW473 细胞系相比，DAOY 和 ONS-76 细胞系中显著过表达的各种 HOX 基因中，选择 HOXA10 和 HOXB4 进行进一步分析。通过实时 PCR 验证了这些 HOX 基因的表达水平。使用小鼠模型研究了 HOXA10 和 HOXB4 基因对 MB 细胞系体内致瘤潜能以及体外增殖和迁移潜能的影响。我们的结果表明，DAOY 细胞系中 HOXA10 的抑制导致体外细胞迁移增加，而体外细胞增殖或体内致瘤潜能不受影响。我们还观察到，UW473 细胞系中 HOXB4 的诱导表达显著降低了 UW473 细胞的体外增殖和迁移能力，而对体内致瘤性没有影响。这表明 HOXA10 在迁移事件中发挥作用，HOXB4 基因参与了 MB 细胞的增殖和迁移过程，但是这些基因似乎不是这些细胞致瘤过程所必需的。
