Adrenocortical development and cancer: focus on SF-1

Lalli, Enzo

doi:10.1677/jme-09-0143

Cited by 43 publications

(33 citation statements)

References 68 publications

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“…SF-1 has been linked to adrenocortical cancer in general and to childhood adrenocortical tumors (ACTs) in particular [13]. Studies have shown that SF-1 is overexpressed in childhood ACTs compared to normal adrenal tissue [4], [5] and that in NCI-H295R cells overexpression of SF-1 leads to increased proliferation and tumor growth [48].…”

Section: Resultsmentioning

confidence: 99%

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Knockdown of SF-1 and RNF31 Affects Components of Steroidogenesis, TGFβ, and Wnt/β-catenin Signaling in Adrenocortical Carcinoma Cells

et al. 2012

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The orphan nuclear receptor Steroidogenic Factor-1 (SF-1, NR5A1) is a critical regulator of development and homeostasis of the adrenal cortex and gonads. We recently showed that a complex containing E3 ubiquitin ligase RNF31 and the known SF-1 corepressor DAX-1 (NR0B1) interacts with SF-1 on target promoters and represses transcription of steroidogenic acute regulatory protein (StAR) and aromatase (CYP19) genes. To further evaluate the role of SF-1 in the adrenal cortex and the involvement of RNF31 in SF-1-dependent pathways, we performed genome-wide gene-expression analysis of adrenocortical NCI-H295R cells where SF-1 or RNF31 had been knocked down using RNA interference. We find RNF31 to be deeply connected to cholesterol metabolism and steroid hormone synthesis, strengthening its role as an SF-1 coregulator. We also find intriguing evidence of negative crosstalk between SF-1 and both transforming growth factor (TGF) β and Wnt/β-catenin signaling. This crosstalk could be of importance for adrenogonadal development, maintenance of adrenocortical progenitor cells and the development of adrenocortical carcinoma. Finally, the SF-1 gene profile can be used to distinguish malignant from benign adrenocortical tumors, a finding that implicates SF-1 in the development of malignant adrenocortical carcinoma.

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Section: Resultsmentioning

confidence: 99%

“…Functionally, SF-1 is known to transcriptionally regulate the expression of genes involved in steroid hormone synthesis and cellular cholesterol homeostasis [12]. However, less is known about SF-1's mechanisms of action and target genes in proliferation and differentiation during development and cancer [13].…”

Section: Introductionmentioning

confidence: 99%

Knockdown of SF-1 and RNF31 Affects Components of Steroidogenesis, TGFβ, and Wnt/β-catenin Signaling in Adrenocortical Carcinoma Cells

et al. 2012

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“…Overexpression of transcription factor SF-1 is an important factor in the pathogenesis of adrenocortical tumors (2)(3)(4)16). Transgenic overexpression of Sf-1 in mice induces the development of adrenocortical neoplastic lesions that express gonadal markers (Gata-4, Amh) (4) and are probably derived from pluripotent adrenogonadal precursor cells lying beneath the outer adrenal connective capsule, which also have the potential to differentiate into cells of gonadal stroma phenotype (termed A cells) in mouse strains susceptible to gonadectomy-induced adrenocortical tumorigenesis (17).…”

Section: Discussionmentioning

confidence: 99%

Vanin-1 Inactivation Antagonizes the Development of Adrenocortical Neoplasia in Sf-1 Transgenic Mice

et al. 2014

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SF-1 (NR5A1) overexpression can induce adrenocortical tumor formation in transgenic mice and is associated with more severe prognosis in patients with adrenocortical cancer. In this study we have identified Vanin-1 (Vnn1), a SF-1 target gene, as a novel modulator of the tumorigenic effect of Sf-1 overexpression in the adrenal cortex. Vanin-1 is endowed with pantetheinase activity, releasing cysteamine in tissues and regulating cell response to oxidative stress by modulating the production of glutathione. Sf-1 transgenic mice developed adrenocortical neoplastic lesions (both dysplastic and nodular) with a frequency increasing with age. Genetic ablation of the Vnn1 gene in Sf-1 transgenic mice significantly reduced the severity of neoplastic lesions in the adrenal cortex. This effect could be reversed by treatment of Sf-1 transgenic/Vnn1 null mice with cysteamine. These data show that alteration of the mechanisms controlling intracellular redox and detoxification mechanisms is relevant to the pathogenesis of adrenocortical neoplasia induced by SF-1 overexpression.

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“…Conversely, high JAG1 expression correlates with longer DFS and OS in ACC ); • matrix metalloproteinase type 2 (MMP-2) contributes to mediate the process of extracellular matrix degradation by cancer cells. Overexpression of this enzyme involved in metastatic invasion is associated with reduced DFS and OS (Volante et al 2006); • staining for phospho-histone H3, a marker for mitotic cells, was shown to have a borderline correlation with OS in ACC, which was less significant than mitotic count (Duregon et al 2014a); • low expression of serum glucocorticoid kinase 1 (SGK1), an ubiquitous serine/threonine kinase regulated by growth factors, is correlated with shorter OS in ACC (Ronchi et al 2012); • Steroidogenic Factor-1 (SF-1) is a transcription factor, belonging to the nuclear receptor superfamily, that has an essential role in the development of adrenal glands and gonads (Lalli 2010). SF-1 expression is a hallmark of ACT and its higher expression levels in ACC are associated with reduced DFS and OS (Sbiera et al 2010, Duregon et al 2013b.…”

Section: Immunohistochemical Markers Improve Prognostic Assessment Inmentioning

confidence: 99%

The next step: mechanisms driving adrenocortical carcinoma metastasis

Lalli

Luconi²

2018

Endocrine-Related Cancer

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Endocrine tumors have the peculiarity to become clinically evident not only due to symptoms related to space occupation by the growing lesion, similarly to most other tumors, but also, and most often, because of their specific hormonal secretion, which significantly contributes to their pathological burden. Malignant endocrine tumors, in addition, have the ability to produce distant metastases. Here, we critically review the current knowledge about mechanisms and biomarkers characterizing the metastatic process in adrenocortical carcinoma (ACC), a rare endocrine malignancy with a high risk of relapse and metastatization even when the primary tumor is diagnosed and surgically removed at an early stage. We highlight perspectives of future research in the domain and possible new therapeutic avenues based on targeting factors having an important role in the metastatic process of ACC.

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Adrenocortical development and cancer: focus on SF-1

Cited by 43 publications

References 68 publications

Knockdown of SF-1 and RNF31 Affects Components of Steroidogenesis, TGFβ, and Wnt/β-catenin Signaling in Adrenocortical Carcinoma Cells

Knockdown of SF-1 and RNF31 Affects Components of Steroidogenesis, TGFβ, and Wnt/β-catenin Signaling in Adrenocortical Carcinoma Cells

Vanin-1 Inactivation Antagonizes the Development of Adrenocortical Neoplasia in Sf-1 Transgenic Mice

The next step: mechanisms driving adrenocortical carcinoma metastasis

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