A transcriptomic signature mediated by HOXA9 promotes human glioblastoma initiation, aggressiveness and resistance to temozolomide

Pojo, Marta; Gonçalves, Céline S.; Xavier‐Magalhães, Ana; Oliveira, Ana I.; Gonçalves, Tiago; Correia, Sara; Rodrigues, Ana João; Costa, Sónia; Pinto, Luís; Pinto, Afonso A.; Lopes, José Manuel; Reis, Rui Manuel; Rocha, Miguel; Sousa, Nuno; Costa, Bruno M.

doi:10.18632/oncotarget.3150

Cited by 48 publications

(70 citation statements)

References 51 publications

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“…Similarly, Ko et al asserted that the HOXA9 expression in epithelial ovarian cancer cells promised a comfortable environment for tumour growth [55]. The work performed by Pojo et al discovered that HOXA9 promoted human glioblastoma initiation and aggressiveness [56]. In terms of the promoter role of HOXA9 during OSCC development and progression, our results verified that miR-139-5p suppressed OSCC cell viability, proliferation, invasion and migration by directly inhibiting HOXA9.…”

Section: Discussionsupporting

confidence: 78%

MiR‐139‐5p inhibits the tumorigenesis and progression of oral squamous carcinoma cells by targeting HOXA9

Wang

Jin

et al. 2017

J Cellular Molecular Medi

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Our study sought to clarify the effects of microRNA‐139‐5p (miR‐139‐5p) in the tumorigenesis and progression of oral squamous cell carcinoma (OSCC) by regulating HOXA9. MiR‐139‐5p and HOXA9 expression in OSCC tissues, tumour adjacent tissues, OSCC cells and normal cells were tested by qRT‐PCR. SAS and CAL‐27 cell lines were selected in among four OSCC cell lines and then transfected with miR‐139‐5p mimics, pEGFP‐HOXA9 and cotransfected with miR‐139‐5p mimics + pEGFP‐HOXA9. We used MTT, colony formation, transwell and wound healing assays to analyse cell viability, proliferation, invasion and migration. The target relationship between miR‐139‐5p and HOXA9 was verified by luciferase reporter assay and Western blot, respectively. MiR‐139‐5p was down‐regulated, whereas HOXA9 was up‐regulated in OSCC tissues and cells. The proliferation, invasion and migration ability of SAS and CAL‐27 cells in miR‐139‐5p mimics group were significantly weaker than those in the control group and the miR‐NC group (P < 0.01). MiR‐139‐5p can negatively regulate HOXA9. The proliferation, invasion and migration of SAS and CAL‐27 cells in the miR‐139‐5p mimics + pEGFP‐HOXA9 group were not significantly different from those in the blank control and negative control groups (P > 0.05). Our results indicated that miR‐139‐5p could directly inhibit HOXA9, which might be a potential mechanism in inhibiting the proliferation, invasiveness and migration of OSCC cells.

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Section: Discussionsupporting

confidence: 78%

MiR‐139‐5p inhibits the tumorigenesis and progression of oral squamous carcinoma cells by targeting HOXA9

Wang

Jin

et al. 2017

J Cellular Molecular Medi

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“…For intracranial models, a total of 2×10 5 U87-MG cells were stereotactically injected in the brain striatum (1.8mm medial-lateral right, 0.4mm anterior-posterior, and 2.5mm dorsal-ventral from the bregma) of 8 weeks old athymic nude Foxn1 nu male mice, as previously described [52]. Animal body weight was evaluated 3 times per week, and general behavior and symptomatology daily.…”

Section: Methodsmentioning

confidence: 99%

Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas

et al. 2016

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BackgroundGlioblastomas (GBM) present a high cellular heterogeneity with conspicuous necrotic regions associated with hypoxia, which is related to tumor aggressiveness. GBM tumors exhibit high glycolytic metabolism with increased lactate production that is extruded to the tumor microenvironment through monocarboxylate transporters (MCTs). While hypoxia-mediated regulation of MCT4 has been characterized, the role of MCT1 is still controversial. Thus, we aimed to understand the role of hypoxia in the regulation of MCT expression and function in GBM, MCT1 in particular.MethodsExpression of hypoxia- and glycolytic-related markers, as well as MCT1 and MCT4 isoforms was assessed in in vitro and in vivo orthotopic glioma models, and also in human GBM tissues by immunofluorescence/immunohistochemistry and Western blot. Following MCT1 inhibition, either pharmacologically with CHC (α-cyano-4-hydroxynnamic acid) or genetically with siRNAs, we assessed GBM cell viability, proliferation, metabolism, migration and invasion, under normoxia and hypoxia conditions.ResultsHypoxia induced an increase in MCT1 plasma membrane expression in glioma cells, both in in vitro and in vivo models. Additionally, treatment with CHC and downregulation of MCT1 in glioma cells decreased lactate production, cell proliferation and invasion under hypoxia. Moreover, in the in vivo orthotopic model and in human GBM tissues, there was extensive co-expression of MCT1, but not MCT4, with the GBM hypoxia marker CAIX.ConclusionHypoxia-induced MCT1 supports GBM glycolytic phenotype, being responsible for lactate efflux and an important mediator of cell survival and aggressiveness. Therefore, MCT1 constitutes a promising therapeutic target in GBM.

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“…Among them, we found 12 potential binding sites for homeobox proteins, including two for HOXA9 (Fig. A), which, interestingly, we previously showed to present various oncogenic roles and to be a prognostic biomarker in GBM patients (Costa et al , ; Pojo et al , ). Interestingly, a putative link between HOXA9 and WNT6 has never been described.…”

Section: Resultsmentioning

confidence: 99%

“…( n = 3 independent assays; mean ± SD; *** P < 0.001, two‐sided unpaired t ‐test). (E) GSEA querying the transcriptome of HOXA9 in U87 cells (Pojo et al, ), highlighting gene expression signatures associated with WNT signaling.…”

Section: Resultsmentioning

confidence: 99%

“…Although DNA methylation was clearly associated with WNT6 expression in glioma, this association was not universal. After ruling out the potential regulation of WNT6 by CAV1, UCA1 , and PLAGL2 in GBM (contrasting to what was previously described in gastric, bladder, and colorectal cancers (Fan et al , ; Li et al , ; Yuan et al , )), we showed that HOXA9, an oncogenic transcription factor whose expression has been associated with increased GBM aggressiveness (impacting on several hallmarks of cancer, increasing cell viability, migration, resistance to TMZ, and tumor growth in a subcutaneous mouse model, while decreasing mice OS in an orthotopic mouse model) and patients’ poor survival (Costa et al , ; Pojo et al , ), is one of the WNT6 transcriptional regulators in GBM (Fig. ), binding to its promoter region.…”

Section: Discussionmentioning

confidence: 99%

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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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A transcriptomic signature mediated by HOXA9 promotes human glioblastoma initiation, aggressiveness and resistance to temozolomide

Cited by 48 publications

References 51 publications

MiR‐139‐5p inhibits the tumorigenesis and progression of oral squamous carcinoma cells by targeting HOXA9

MiR‐139‐5p inhibits the tumorigenesis and progression of oral squamous carcinoma cells by targeting HOXA9

Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas

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

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