A general method to derive robust organ-specific gene expression-based differentiation indices: application to thyroid cancer diagnostic

Tomás, Gil; Tarabichi, Maxime; Gacquer, David; Hebrant, Aline; Dom, Geert; Dumont, Jacques Emile; Keutgen, Xavier M.; Fahey, Thomas J.; Maenhaut, Carine; Detours, Vincent

doi:10.1038/onc.2011.626

Cited by 109 publications

(85 citation statements)

References 35 publications

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“…PROX1 downregulation in thyroid cancers was also confirmed using another set of thyroid cancer gene profiling study (Figure 1B) (12). Moreover, we performed analyses against additional public repositories (13–16) to investigate PROX1 expression through NextBio Disease Atlas (9) and consistently found PROX1 downregulation in various thyroid cancers (Figure 1C). Moreover, PROX1 mRNA level was compared in PTCs vs. their adjacent normal tissues from the same patients using Gene Expression Omnibus (GEO) statistical tool against two independent data sets (GSE3467, GSE3678), which revealed PROX1 downregulation in PTCs relative to their matched normal tissues (Figure 1D,E).…”

Section: Resultsmentioning

confidence: 90%

Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells

et al. 2016

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Papillary thyroid cancer (PTC) is one of the most common endocrine malignancies associated with significant morbidity and mortality. Although multiple studies have contributed to a better understanding of the genetic alterations underlying this frequently arising disease, the downstream molecular effectors that impact PTC pathogenesis remain to be further defined. Here, we report that the regulator of cell fate specification, PROX1, becomes inactivated in PTC through mRNA downregulation and cytoplasmic mislocalization. Expression studies in clinical specimens revealed that aberrantly activated NOTCH signaling promoted PROX1 downregulation and that cytoplasmic mislocalization significantly altered PROX1 protein stability. Importantly, restoration of PROX1 activity in thyroid carcinoma cells revealed that PROX1 not only enhanced Wnt/β-catenin signaling, but also regulated several genes known to be associated with PTC, including thyroid cancer protein (TC)-1, SERPINA1, and FABP4. Furthermore, PROX1 re-expression suppressed the malignant phenotypes of thyroid carcinoma cells, such as proliferation, motility, adhesion, invasion, anchorage-independent growth, and polyploidy. Moreover, animal xenograft studies demonstrated that restoration of PROX1 severely impeded tumor formation and suppressed the invasiveness and the nuclear/cytoplasmic ratio of PTC cells. Taken together, our findings demonstrate that NOTCH-induced PROX1 inactivation significantly promotes the malignant behavior of thyroid carcinoma, and suggest that PROX1 reactivation may represent a potential therapeutic strategy to attenuate disease progression

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Section: Resultsmentioning

confidence: 90%

Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells

et al. 2016

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“…It is supported by a measurable expression program switch that affects all gene categories [3]. We argue that this should be another, if not the major, 'hallmark' of a cancerous cell, and it has been shown to be a robust diagnostic index for thyroid tumors [4].…”

Section: The Concept Of a Hallmark (See Glossary)mentioning

confidence: 98%

Hallmarks of cancer: of all cancer cells, all the time?

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Dumont

Maenhaut

et al. 2012

Trends in Molecular Medicine

116

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“…The 6 unprocessed gene expression profiles that met the inclusion criteria of this study were downloaded from the Gene Expression Omnibus (GEO, http://www.ncbi. nlm.nih.gov/geo/) database: GSE6004 [22], GSE58545 [23], GSE27155 [24,25], GSE53157 [26], GSE60542 [27] and GSE33630 [28,29]. The relevant data are shown in Table 1.…”

Section: Thyroid Cancer Gene Expression Datasets Collection and Identmentioning

confidence: 99%

Identification of hub genes in papillary thyroid carcinoma: robust rank aggregation and weighted gene co-expression network analysis

et al. 2020

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Background: Papillary thyroid carcinoma (PTC), which is the most common endocrine malignancy, has been steadily increasing worldwide in incidence over the years, while mechanisms underlying the pathogenesis and diagnostic for PTC are incomplete. The purpose of this study is to identify potential biomarkers for diagnosis of PTC, and provide new insights into pathogenesis of PTC.Methods: Based on weighted gene co-expression network analysis, Robust Rank Aggregation, functional annotation, GSEA and DNA methylation, were employed for investigating potential biomarkers for diagnosis of PTC.Results: Black and turquoise modules were identified in the gene co-expression network constructed by 1807 DEGs that from 6 eligible gene expression profiles of Gene Expression Omnibus database based on Robust Rank Aggregation and weighted gene co-expression network analysis. Hub genes were significantly down-regulated and the expression levels of the hub genes were different in different stages in hub gene verification. ROC curves indicated all hub genes had good diagnostic value for PTC (except for ABCA6 AUC = 89.5%, the 15 genes with AUC > 90%). Methylation analysis showed that hub gene verification ABCA6, ACACB, RMDN1 and TFPI were identified as differentially methylated genes, and the decreased expression level of these genes may relate to abnormal DNA methylation. Moreover, the expression levels of 8 top hub genes were correlated with tumor purity and tumor-infiltrating immune cells. These findings, including functional annotations and GSEA provide new insights into pathogenesis of PTC. Conclusions:The hub genes and methylation of hub genes may as potential biomarkers provide new insights for diagnosis of PTC, and all these findings may be the direction to study the mechanisms underlying of PTC in the future.

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A general method to derive robust organ-specific gene expression-based differentiation indices: application to thyroid cancer diagnostic

Cited by 109 publications

References 35 publications

Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells

Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells

Hallmarks of cancer: of all cancer cells, all the time?

Identification of hub genes in papillary thyroid carcinoma: robust rank aggregation and weighted gene co-expression network analysis

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