Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Mol Oncol. 2020 Jun;14(6):1224-1241. doi: 10.1002/1878-0261.12633. Epub 2020 May 6.
Despite much effort to improve treatments, patients with malignant glioma still present a very poor prognosis that has not changed significantly in the last decades. In this context, it is crucial to better understand glioma pathogenesis to identify new molecular prognostic subgroups and therapeutic targets. WNT6 was recently identified as a new oncogenic molecule in glioblastoma (GBM), with prognostic value in patients, but the mechanisms underlying WNT6 aberrant expression in glioma are still unknown. WNT6 was overexpressed in a subset of gliomas independently of IDH mutations, 1p/19q codeletion status, and WNT6 gene copy number. Interestingly, WNT6 expression is associated with the DNA methylation levels of particular CpG regions at both the WNT6 promoter and the gene body in glioma patient samples. HOXA9, a transcription factor previously associated with poorer clinical outcome in GBM, was identified as a novel transcriptional regulator of WNT6, activating the WNT/β-catenin pathway in vitro and in vivo. In various cohorts of glioma patients, mRNA levels of WNT6 and HOXA9 were significantly correlated, extending our in vitro and in vivo findings into the clinical setting. Interestingly, this novel molecular link between WNT6 and HOXA9 was not limited to glioma, as they were co-expressed also in patients with other tumor types. Clinically, WNT6 was a prognostic biomarker of shorter survival in GBM, independently of HOXA9 expression. Concomitant high expression of both WNT6 and HOXA9 identified a subgroup of patients with particularly dismal survival. These findings describe novel WNT6 regulatory mechanisms in GBM, establishing particular DNA methylation patterns and HOXA9 as critical regulators of WNT6 expression in glioma. This HOXA9-WNT6 molecular link supports WNT signaling in GBM cells and is a powerful prognostic biomarker, highlighting the clinical relevance of this axis in patients. Novel therapies targeting WNT6-HOXA9 signaling may thus be useful for this deadly disease.
尽管人们努力改善治疗方法，但恶性胶质瘤患者的预后仍然很差，在过去几十年中并没有显著改善。在这种情况下，更好地了解胶质瘤的发病机制以确定新的分子预后亚组和治疗靶点至关重要。WNT6 最近被确定为胶质母细胞瘤（GBM）中的一种新的致癌分子，对患者具有预后价值，但 WNT6 在胶质瘤中异常表达的机制尚不清楚。WNT6 在一组胶质瘤中表达过度，与 IDH 突变、1p/19q 缺失状态和 WNT6 基因拷贝数无关。有趣的是，WNT6 的表达与胶质瘤患者样本中 WNT6 启动子和基因体的特定 CpG 区域的 DNA 甲基化水平相关。HOXA9 是一种先前与 GBM 临床结局较差相关的转录因子，被鉴定为 WNT6 的新型转录调节因子，在体外和体内激活 WNT/β-catenin 通路。在不同的胶质瘤患者队列中，WNT6 和 HOXA9 的 mRNA 水平显著相关，将我们的体外和体内发现扩展到临床环境中。有趣的是，WNT6 和 HOXA9 之间的这种新的分子联系不仅限于胶质瘤，因为它们在其他肿瘤类型的患者中也有共表达。临床上，WNT6 是 GBM 患者生存率较短的预后生物标志物，与 HOXA9 表达无关。同时表达高 WNT6 和 HOXA9 确定了一组生存特别差的患者。这些发现描述了 GBM 中 WNT6 的新调节机制，确定了特定的 DNA 甲基化模式和 HOXA9 作为胶质瘤中 WNT6 表达的关键调节因子。该 HOXA9-WNT6 分子联系支持 GBM 细胞中的 WNT 信号，并作为一种强大的预后生物标志物，突出了该轴在患者中的临床相关性。针对 WNT6-HOXA9 信号的新型治疗方法可能对这种致命疾病有用。
