<i>WNT6</i> is a novel oncogenic prognostic biomarker in human glioblastoma

Gonçalves, Céline S.; Castro, Joana Isabel Martins Cosme Vieira; Pojo, Marta; Martins, Eduarda P.; Queirós, Sandro; Chautard, Emmanuel; Taipa, Ricardo; Pires, Manuel Melo; Pinto, Afonso A.; Pardal, Fernando; Custódia, Carlos; Faria, Cláudia C.; Clara, Carlos Afonso; Reis, Rui Manuel; Sousa, Nuno; Costa, Bruno M.

doi:10.7150/thno.25025

Cited by 35 publications

(52 citation statements)

References 70 publications

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“…Whether this mechanism also occurs or is deregulated in glioma remains to be explored. Recently, Gonçalves et al [184] demonstrated that WNT6, a ligand and activator of the WNT pathway, which displays oncogenic functions in GBM [185], is transcriptionally regulated by HOXA9, identifying a novel link between HOX and WNT signalling.…”

Section: Hoxa5mentioning

confidence: 99%

HOX gene cluster (de)regulation in brain: from neurodevelopment to malignant glial tumours

Gonçalves

Boiteux

Arnaud

et al. 2020

Cell. Mol. Life Sci.

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HOX genes encode a family of evolutionarily conserved homeodomain transcription factors that are crucial both during development and adult life. In humans, 39 HOX genes are arranged in four clusters (HOXA, B, C, and D) in chromosomes 7, 17, 12 and 2, respectively. During embryonic development, particular epigenetic states accompany their expression along the anterior-posterior body axis. This tightly regulated temporal-spatial expression pattern reflects their relative chromosomal localization, and is critical for normal embryonic brain development, when HOX genes are mainly expressed in the hindbrain and mostly absent in the forebrain region. Epigenetic marks, mostly polycombassociated, are dynamically regulated at HOX loci and regulatory regions to ensure the finely tuned HOX activation and repression, highlighting a crucial epigenetic plasticity necessary for homeostatic development. HOX genes are essentially absent in healthy adult brain, whereas they are detected in malignant brain tumours, namely gliomas, where HOX genes display critical roles by regulating several hallmarks of cancer. Here, we review the major mechanisms involved in HOX genes (de)regulation in the brain, from embryonic to adult stages, in physiological and oncologic conditions. We focus particularly on the emerging causes of HOX gene deregulation in glioma, as well as on their functional and clinical implications.

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Section: Hoxa5mentioning

confidence: 99%

HOX gene cluster (de)regulation in brain: from neurodevelopment to malignant glial tumours

Gonçalves

Boiteux

Arnaud

et al. 2020

Cell. Mol. Life Sci.

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“…). Interestingly, when performing GSEA to identify transcriptomic signatures reminiscent of WNT6 ‐associated genes in GBM patients (Gonçalves et al , ), we found that WNT6 ‐negatively correlated genes were enriched for genes upregulated in LAML cells upon HOXA9 knockdown [enrichment score (ES) = −0.26 and false discovery rate, FDR = 0.18; Fig. ], further supporting this novel molecular link between HOXA9 and WNT6.…”

Section: Resultsmentioning

confidence: 99%

A novel molecular link between HOXA9 and WNT6 in glioblastoma identifies a subgroup of patients with particular poor prognosis

et al. 2020

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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/b-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 Abbreviations 5-Aza, 5-aza-2'-deoxycytidine; ACC, adrenocortical carcinoma; BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma

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“…In 1982, for the first time, Nusse and Varmus described WNT-1 (Int-1) as an oncogene in mouse mammary tumors [35]. Up to now, increasing evidences suggested that defective WNT signaling is a causative factor in various cancers including breast cancer [36][37][38], lung cancer [39], pancreas cancer [40], colorectal cancer [41], hepatocellular carcinoma [42] and as well as glioma [6,8,14]. Despite the fact that some members of WNTs have been confirmed to play crucial roles in glioma, our study is first to investigate expression patterns, prognostic significance, and potential function of all the 19 WNT family members in glioma.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, WNT5A was found to induce rapid growth and migration of glioma and associated with the presence of tumor-associated microglia [8,9,13,14]. WNT6 expression was shown to increase the features of glioma aggressiveness [6]. WNT7A and WNT7B was shown to regulate glioma-vascular interactions [7].…”

Section: Introductionmentioning

confidence: 99%

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Expression profiles and prognostic significance of WNT family members in glioma via bioinformatic analysis

Yang

Gao

et al. 2020

Bioscience Reports

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Aims: The dysregulation and essential role of WNTs in glioma have been widely implicated. However, there is a paucity of literature on the expression status of all the 19 WNTs in glioma. Our study was aimed to evaluate the expression and prognostic values of the 19 WNTs in glioma. Methods: mRNA expression and clinical data were retrieved from the Cancer Genome Atlas (TCGA) database, Chinese Glioma Genome Atlas (CGGA), GTEx and ONCOMINE databases. The 50 frequent neighbor genes of WNT5A and WNT10B were shown with PPI network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Results: We found that the mRNA expression of WNT5A was significantly higher in glioma; however, the WNT10B expression was significantly lower in glioma. Furthermore, the expression of WNT5A and WNT10B was associated with the clinicopathology of glioma. The survival analysis revealed that the higher expressions of WNT5A and WNT16 were associated poor overall survival (OS) in patients with glioma. Conversely, overexpression of WNT3, WNT5B, and WNT10B was associated with better OS. Finally, Go and KEGG analysis revealed WNT5A was associated with multiple signal translations, and crucial oncogenes (EGFR and MDM2) and 2 important tumor suppressors (PTEN and IKN4a/ARF) were found closely correlated with WNT5A in glioma. Conclusion: Among 19WNTs, WNT5A can serve as a candidate to diagnose and therapy glioma, while WNT10B might be valuable for anti-glioma research. The presumed direction was provided to explore the relation of WNTs signal and multiple pathways in glioma.

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WNT6 is a novel oncogenic prognostic biomarker in human glioblastoma

Cited by 35 publications

References 70 publications

HOX gene cluster (de)regulation in brain: from neurodevelopment to malignant glial tumours

HOX gene cluster (de)regulation in brain: from neurodevelopment to malignant glial tumours

A novel molecular link between HOXA9 and WNT6 in glioblastoma identifies a subgroup of patients with particular poor prognosis

Expression profiles and prognostic significance of WNT family members in glioma via bioinformatic analysis

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