Identification of Potential Gene Markers and Insights into the Pathophysiology of Pheochromocytoma Malignancy

Thouënnon, Erwan; Elkahloun, Abdel G.; Guillemot, Johann; Gimenez-Roqueplo, Anne-Paule; Bertherat, Jérôme; Aimar, Pierre; Ghzili, Hafida; Grumolato, Luca; Mureşan, Mihaela; Klein, Marc; Lefebvre, Henri; Ouafik, L’Houcine; Vaudry, Hubert; Plouin, Pierre‐François; Yon, Laurent; Anouar, Youssef

doi:10.1210/jc.2007-1253

Cited by 61 publications

(51 citation statements)

References 18 publications

(17 reference statements)

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“…Brouwers et al 38 examined 20 malignant tumors along with 70 sporadic and syndromic benign tumors: Gene Ontology Analysis of benign and malignant tumor comparison revealed the relevance of signal transduction changes. The significant gene sets established in two recent large-scale studies by Thouënnon et al 39 and Suh et al 40 are quite different, which indicates the need for further, large-scale gene expression profiling studies.…”

Section: Discussionmentioning

confidence: 96%

“…Transcriptomic studies representing targets of miRNA-based regulation are pivotal for the correct interpretation of miRNA findings. There have been six previous studies 11,[37][38][39][40][41] on gene expression profiling involving malignant pheochromocytomas to date. The studies of Dahia et al, 11 Björklund et al 37 and the most recent study of Waldmann et al 41 included only two, three and five malignant pheochromocytomas, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…38,39 Among the downregulated mRNAs of Thouënnon's study, we have identified in silico predicted targets of miR-1225-3p overexpressed in recurring tumors eg ankyrin-1 (ANK1), protein kinase C-e (PRKCE), nuclear receptor interacting protein 2 (NRIP2).…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

et al. 2010

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MicroRNAs are involved in the pathogenesis of several tumors, however, there have been no data on microRNA expression in pheochromocytomas to date. The objective of our study was to perform microRNA expression profiling in sporadic and hereditary benign, and recurring adrenomedullary tumors. Furthermore, the applicability of formalin-fixed paraffin-embedded tissue samples for the analysis of microRNA expression in pheochromocytomas was examined. MicroRNA expression data of three matched frozen and formalin-fixed paraffin-embedded samples were correlated. A total of 21 formalin-fixed paraffin-embedded samples (sporadic benign, multiple endocrine neoplasia 2, von Hippel-Lindau disease, sporadic recurring) were subjected to microRNA expression profiling using microarrays. MicroRNAs with significant differences in expression were validated and sample sizes were extended including tumors from neurofibromatosis type 1 patients by real-time quantitative reverse-transcription PCR (n ¼ 33). MicroRNA target prediction was carried out by TargetScan and MicroCosm Targets. Pathway analysis of targets was performed by Ingenuity Pathway Analysis and DIANA mirPath. Furthermore, microRNA expression profiles of a malignant pheochromocytoma and a pair of primary and recurrent tumors were studied by TaqMan Human MicroRNA Cards. MicroRNA expression correlated well between frozen and formalin-fixed paraffinembedded samples (70-92%). Microarray analysis revealed 16 significantly differentially expressed microRNAs. Five of these were validated by real-time RT-PCR. miR-139-3p, miR-541 and miR-765 were significantly differentially expressed between sporadic benign and von Hippel-Lindau-related pheochromocytomas. Significantly higher expression of miR-885-5p and miR-1225-3p was found in multiple endocrine neoplasia type 2 and sporadic recurring pheochromocytomas, respectively. Pathway analysis revealed the possible involvement of Notch-and G-proteincoupled receptor signaling in tumor recurrence. MicroRNA expression profiles in the primary recurrent and recurring malignant comparisons have been similar. In conclusion, we have proved that formalin-fixed paraffinembedded samples can be used for the analysis of microRNA expression in pheochromocytomas. MicroRNA expression patterns differ between various sporadic, hereditary and recurring tumors and miR-1225-3p may be useful for identifying recurring pheochromocytomas.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

et al. 2010

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“…Loss of expression of members of this family of proteins has been observed in a number of tumour types, including QPCT itself in melanoma (Muthusamy et al, 2006) and phaeochromocytomas (Thoue¨nnon et al, 2007). SCUBE (Signal peptide CUB EGF-like domain-containing protein) genes encode a small group of secreted plasma membrane-associated proteins characterised by an N-terminal signal peptide sequence, multiple EGF (epidermal growth factor) domains, a large spacer region containing multiple N-linked glycosylation sites and a C-terminal CUB (Complement subcomponent C1r/C1s EGF-related sea Urchin protein, Bone morphogenetic protein1) domain (Grimmond et al, 2000).…”

Section: Ct Bstu1mentioning

confidence: 99%

Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma

et al. 2010

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The detection of promoter region hypermethylation and transcriptional silencing has facilitated the identification of candidate renal cell carcinoma (RCC) tumour suppressor genes (TSGs). We have used a genome-wide strategy (methylated DNA immunoprecipitation (MeDIP) and whole-genome array analysis in combination with highdensity expression array analysis) to identify genes that are frequently methylated and silenced in RCC. MeDIP analysis on 9 RCC tumours and 3 non-malignant normal kidney tissue samples was performed, and an initial shortlist of 56 candidate genes that were methylated by array analysis was further investigated; 9 genes were confirmed to show frequent promoter region methylation in primary RCC tumour samples (KLHL35 (39%), QPCT (19%), SCUBE3 (19%), ZSCAN18 (32%), CCDC8 (35%), FBN2 (34%), ATP5G2 (36%), PCDH8 (58%) and CORO6 (22%)). RNAi knockdown for KLHL35, QPCT, SCUBE3, ZSCAN18, CCDC8 and FBN2 resulted in an anchorage-independent growth advantage. Tumour methylation of SCUBE3 was associated with a significantly increased risk of cancer death or relapse (P ¼ 0.0046). The identification of candidate epigenetically inactivated RCC TSGs provides new insights into renal tumourigenesis.

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“…In a previous study, we have shown the differential expression in benign versus malignant pheochromocytomas of peptidylglycine a-amidating monooxygenase (PAM), the enzyme responsible for the amidation and therefore the stability as well as the activity of PACAP, NPY, and AM (Thouennon et al 2007), suggesting a potential alteration of the function of these amidated peptides. Because these peptides exert proliferative and/or anti-apoptotic effects on various cell types, positively regulate catecholamine secretion from chromaffin cells in physiological or pathophysiological conditions, and can be linked to angiogenesis which represents an important feature of tumorigenesis, especially in tumors exhibiting high vascularization such as pheochromocytomas, we carried out in the present study a systematic quantitative survey of the expression of these trophic peptides and their receptors in benign and malignant pheochromocytomas.…”

Section: Introductionmentioning

confidence: 99%

Expression of trophic amidated peptides and their receptors in benign and malignant pheochromocytomas: high expression of adrenomedullin RDC1 receptor and implication in tumoral cell survival

Thouënnon¹,

Aimar²,

Tanguy³

et al. 2010

Endocrine-Related Cancer

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Pheochromocytomas are catecholamine-producing tumors which are generally benign, but which can also present as or develop into malignancy. Molecular pathways of malignant transformation remain poorly understood. Pheochromocytomas express various trophic peptides which may influence tumoral cell behavior. Here, we investigated the expression of trophic amidated peptides, including pituitary adenylate cyclase-activating polypeptide (PACAP), neuropeptide Y (NPY), and adrenomedullin (AM), and their receptors in benign and malignant pheochromocytomas in order to assess their potential role in chromaffin cell tumorigenesis and malignant transformation. PACAP, NPY, and AM are expressed in the majority of pheochromocytomas studied; NPY exhibiting the highest mRNA levels relative to reference genes. Although median gene expression or peptide levels were systematically lower in malignant compared to benign tumors, no statistically significant difference was found. Among all the receptors of these peptides that were analyzed, only the AM receptor RDC1 displayed a differential expression between benign and malignant pheochromocytomas. This receptor exhibited a fourfold higher expression in malignant than in benign tumors. AM and stromal cell-derived factor 1, which has also been described as a ligand for RDC1, increased the number of human pheochromocytoma cells in primary culture and exerted anti-apoptotic activity on rat pheochromocytoma PC12 cells. In addition, RDC1 gene silencing decreased the number of viable PC12 cells. This study shows the expression of several trophic peptides and their receptors in benign and malignant pheochromocytomas, and suggests that AM and its RDC1 receptor could be involved in chromaffin cell tumorigenesis through pro-survival effects. Therefore, AM and RDC1 may represent valuable targets for the treatment of malignant pheochromocytomas.

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Identification of Potential Gene Markers and Insights into the Pathophysiology of Pheochromocytoma Malignancy

Abstract: The gene expression profiling of benign and malignant pheochromocytomas clearly identified a set of genes that could be used as a prognostic multi-marker and revealed that the expression of several genes encoding neuroendocrine proteins was reduced in malignant compared with benign tumors.

Cited by 61 publications

References 18 publications

MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma

Expression of trophic amidated peptides and their receptors in benign and malignant pheochromocytomas: high expression of adrenomedullin RDC1 receptor and implication in tumoral cell survival

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