Glioblastoma (GBM) is a universally fatal brain cancer, for which novel therapies targeting specific underlying oncogenic events are urgently needed. While the WNT pathway has been shown to be frequently activated in GBM, constituting a potential therapeutic target, the relevance of WNT6, an activator of this pathway, remains unknown.

Methods: WNT6 protein and mRNA levels were evaluated in GBM. WNT6 levels were silenced or overexpressed in GBM cells to assess functional effects in vitro and in vivo. Phospho-kinase arrays and TCF/LEF reporter assays were used to identify WNT6-signaling pathways, and significant associations with stem cell features and cancer-related pathways were validated in patients. Survival analyses were performed with Cox regression and Log-rank tests. Meta-analyses were used to calculate the estimated pooled effect.

Results: We show that WNT6 is significantly overexpressed in GBMs, as compared to lower-grade gliomas and normal brain, at mRNA and protein levels. Functionally, WNT6 increases typical oncogenic activities in GBM cells, including viability, proliferation, glioma stem cell capacity, invasion, migration, and resistance to temozolomide chemotherapy. Concordantly, in in vivo orthotopic GBM mice models, using both overexpressing and silencing models, WNT6 expression was associated with shorter overall survival, and increased features of tumor aggressiveness. Mechanistically, WNT6 contributes to activate typical oncogenic pathways, including Src and STAT, which intertwined with the WNT pathway may be critical effectors of WNT6-associated aggressiveness in GBM. Clinically, we establish WNT6 as an independent prognostic biomarker of shorter survival in GBM patients from several independent cohorts.

Conclusion: Our findings establish WNT6 as a novel oncogene in GBM, opening opportunities to develop more rational therapies to treat this highly aggressive tumor.

Keywords: biomarker, glioblastoma, oncogene, prognosis, WNT6, WNT pathway

胶质母细胞瘤（GBM）是一种普遍致命的脑癌，迫切需要针对特定​​潜在致癌事件的新型疗法。尽管已显示WNT途径在GBM中经常被激活，构成了潜在的治疗靶标，但WNT6（该途径的激活剂）的相关性仍然未知。

方法：在GBM中评估WNT6蛋白和mRNA水平。WNT6水平被压制或在GBM细胞中过表达，以评估功能效果的体外和体内。使用磷酸激酶阵列和TCF / LEF报告基因检测法鉴定WNT6信号通路，并验证了患者体内与干细胞特征和癌症相关通路的显着相关性。生存分析采用Cox回归和对数秩检验。荟萃分析用于计算估计的合并效应。

结果：我们显示，与低级神经胶质瘤和正常脑相比，WNT6在GBM中在mRNA和蛋白质水平上明显过表达。在功能上，WNT6增加GBM细胞中的典型致癌活性，包括生存力，增殖，神经胶质瘤干细胞能力，侵袭，迁移和对替莫唑胺化学疗法的抗性。一致地，在体内使用过表达和沉默模型的原位GBM小鼠模型，WNT6表达与较短的总生存期和肿瘤侵袭性增加有关。从机制上讲，WNT6有助于激活典型的致癌途径，包括Src和STAT，这些途径与WNT途径交织在一起可能是WNT6相关性GBM侵袭性的关键影响因素。在临床上，我们将WNT6建立为来自多个独立队列的GBM患者生存期较短的独立预后生物标志物。

结论：我们的发现将WNT6确立为GBM中的一种新型致癌基因，为开发更合理的疗法来治疗这种高度侵袭性肿瘤提供了机会。

关键词：生物标志物，胶质母细胞瘤，癌基因，预后，WNT6，WNT途径