Department of Oncology, Children's Research Center, Neuro-Oncology group, University Children's Hospital Zürich, August-Forel Strasse 1, CH-8008, Zürich, Switzerland.
Department of Pediatrics, Ribeirão Preto Medical School, Hospital das Clínicas, University of São Paulo, Av.Bandeirantes 3900, Hospital das Clínicas, Ribeirão Preto, São Paulo, Brazil.
Cancer Gene Ther. 2020 May;27(5):378-382. doi: 10.1038/s41417-019-0100-3. Epub 2019 May 10.
Medulloblastoma (MB) is the most frequent malignant brain tumor in children and it is subgrouped into 4 entities (SHH, WNT, Group 3, and Group 4). Molecular pathways involved in these different subgroups still are evolving and can be of clinical relevance to therapy. The YAP1-CTGF axis is known to regulate cell proliferation, differentiation, and cell death; however, its role in MB is poorly explored. We aimed to investigate the role of YAP1 gene in the MB SHH cell line DAOY and evaluate cell proliferation, doubling time and 3D spheroids invasion and its consequence on CTGF regulation. We assessed CTGF expression from 22 children with MB. Lastly, we validated our findings through in silico analysis in large cohorts dataset of patients. We observed an increased invasion rate of DAOY cells and CTGF downregulation under YAP1 knockdown (p < 0.0001). Additionally CTGF is overexpressed in MB with extensive nodularity subtype and an indicative of higher survival rates in pediatric MB (p < 0.05). Interestingly, no difference of CTGF expression was observed between molecular subgroups. These results provide new evidence ofCTGF as a potential prognostic marker for MB, corroborating to the role of YAP1 in restricting MB cell.
髓母细胞瘤(MB)是儿童中最常见的恶性脑肿瘤,可分为 4 个实体(SHH、WNT、Group 3 和 Group 4)。这些不同亚组中涉及的分子途径仍在不断发展,并可能与治疗的临床相关性有关。YAP1-CTGF 轴已知可调节细胞增殖、分化和细胞死亡;然而,其在 MB 中的作用尚未得到充分探索。我们旨在研究 YAP1 基因在 MB SHH 细胞系 DAOY 中的作用,并评估细胞增殖、倍增时间和 3D 球体侵袭及其对 CTGF 调节的影响。我们评估了 22 名 MB 患儿的 CTGF 表达。最后,我们通过大样本数据集的计算机分析验证了我们的发现。我们观察到 YAP1 敲低后 DAOY 细胞侵袭率增加和 CTGF 下调(p<0.0001)。此外,在具有广泛结节性亚型的 MB 中 CTGF 过表达,并提示儿童 MB 生存率更高(p<0.05)。有趣的是,在分子亚组之间未观察到 CTGF 表达的差异。这些结果为 CTGF 作为 MB 的潜在预后标志物提供了新的证据,证实了 YAP1 在限制 MB 细胞中的作用。