Comprehensive Characterization of the Regulatory Landscape of Adrenocortical Carcinoma: Novel Transcription Factors and Targets Associated with Prognosis

Muzzi, João C. D.; Magno, Jessica Maria; Souza, Jean S.; Alvarenga, Larissa M.; Moura, Juliana de; Figueiredo, Bonald C.; Castro, Mauro A. A.

doi:10.3390/cancers14215279

Cited by 5 publications

(7 citation statements)

References 81 publications

(134 reference statements)

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“…Those studies have been made possible by accessing publicly available transcriptome databases to evaluate the intratumoral microenvironment. Using the RNA-seq and clinical data from 78 samples from the TCGA ACC cohort [ 118 ], Muzzi et al identified 369 regulatory units composed of a TF and its targets, named regulons, associated with OS in multivariate Cox analysis [ 119 ]. Of these 369 units, 346 were also significantly correlated to OS in the European Network for the Study of Adrenal Tumors (ENSAT) cohort with 44 ACC cases [ 120 ].…”

Section: Sf-1 and The Tumor Microenvironment (Tme) In Accmentioning

confidence: 99%

“…Of these 369 units, 346 were also significantly correlated to OS in the European Network for the Study of Adrenal Tumors (ENSAT) cohort with 44 ACC cases [ 120 ]. The NR5A1 regulon represented one of the largest regulons in this analysis with 248 targets [ 119 ]. Overexpression of this TF correlated with low OS in the multivariate Cox and Kaplan–Meier analyses in the TCGA ACC cohort as well as in the ENSAT ACC cohort.…”

Section: Sf-1 and The Tumor Microenvironment (Tme) In Accmentioning

confidence: 99%

“…Interestingly, of the 369 prognostic regulons, the NR5A1 regulon presented the highest negative correlation with the TGF beta response, and a negative correlation with IFN gamma response, lymphocyte infiltration signature, and leukocyte fraction. On the other hand, it was positively correlated with proliferation and wound healing signatures [ 119 ]. These results indicate an association of NR5A1 with immune suppression observed in most ACC cases [ 121 , 122 ] and may be related to the stimulation of steroidogenesis by this TF.…”

Section: Sf-1 and The Tumor Microenvironment (Tme) In Accmentioning

confidence: 99%

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Steroidogenic Factor 1, a Goldilocks Transcription Factor from Adrenocortical Organogenesis to Malignancy

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Doghman

Ruggiero

et al. 2023

IJMS

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Steroidogenic factor-1 (SF-1, also termed Ad4BP; NR5A1 in the official nomenclature) is a nuclear receptor transcription factor that plays a crucial role in the regulation of adrenal and gonadal development, function and maintenance. In addition to its classical role in regulating the expression of P450 steroid hydroxylases and other steroidogenic genes, involvement in other key processes such as cell survival/proliferation and cytoskeleton dynamics have also been highlighted for SF-1. SF-1 has a restricted pattern of expression, being expressed along the hypothalamic-pituitary axis and in steroidogenic organs since the time of their establishment. Reduced SF-1 expression affects proper gonadal and adrenal organogenesis and function. On the other hand, SF-1 overexpression is found in adrenocortical carcinoma and represents a prognostic marker for patients’ survival. This review is focused on the current knowledge about SF-1 and the crucial importance of its dosage for adrenal gland development and function, from its involvement in adrenal cortex formation to tumorigenesis. Overall, data converge towards SF-1 being a key player in the complex network of transcriptional regulation within the adrenal gland in a dosage-dependent manner.

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Section: Sf-1 and The Tumor Microenvironment (Tme) In Accmentioning

confidence: 99%

Section: Sf-1 and The Tumor Microenvironment (Tme) In Accmentioning

confidence: 99%

Section: Sf-1 and The Tumor Microenvironment (Tme) In Accmentioning

confidence: 99%

See 1 more Smart Citation

Steroidogenic Factor 1, a Goldilocks Transcription Factor from Adrenocortical Organogenesis to Malignancy

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Doghman

Ruggiero

et al. 2023

IJMS

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“…Also, CENPA appears positively enriched in the WNT/β-Catenin signaling pathway and acts as the main regulon of Ki-67, a ubiquitous prognostic and proliferative marker widely employed in tumor histopathology ( 41 )(22/22). Herein, we reported that CENPA was up-regulated in PCa tissues, and its overexpression correlated with adverse clinicopathological outcomes in a large cohort ( 42 ).…”

Section: Discussionmentioning

confidence: 97%

Identification of a novel senescence-associated signature to predict biochemical recurrence and immune microenvironment for prostate cancer

Han

Deng²,

Yang³

et al. 2023

Front. Immunol.

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BackgroundProstate cancer (PCa) is an age-associated malignancy with high morbidity and mortality rate, posing a severe threat to public health. Cellular senescence, a specialized cell cycle arrest form, results in the secretion of various inflammatory mediators. In recent studies, senescence has shown an essential role in tumorigenesis and tumor development, yet the extensive effects of senescence in PCa have not been systematically investigated. Here, we aimed to develop a feasible senescence-associated prognosis model for early identification and appropriate management in patients with PCa.MethodThe RNA sequence results and clinical information available from The Cancer Genome Atlas (TCGA) and a list of experimentally validated senescence-related genes (SRGs) from the CellAge database were first obtained. Then, a senescence-risk signature related with prognosis was constructed using univariate Cox and LASSO regression analysis. We calculated the risk score of each patient and divided them into high-risk and low-risk groups in terms of the median value. Furthermore, two datasets (GSE70770 and GSE46602) were used to assess the effects of the risk model. A nomogram was built by integrating the risk score and clinical characteristics, which was further verified using ROC curves and calibrations. Finally, we compared the differences in the tumor microenvironment (TME) landscape, drug susceptibility, and the functional enrichment among the different risk groups.ResultsWe established a unique prognostic signature in PCa patients based on eight SRGs, including CENPA, ADCK5, FOXM1, TFAP4, MAPK, LGALS3, BAG3, and NOX4, and validated well prognosis-predictive power in independent datasets. The risk model was associated with age and TNM staging, and the calibration chart presented a high consistency in nomogram prediction. Additionally, the prognostic signature could serve as an independent prediction factor due to its high accuracy. Notably, we found that the risk score was positively associated with tumor mutation burden (TMB) and immune checkpoint, whereas negatively correlated with tumor immune dysfunction and exclusion (TIDE), suggesting that these patients with risk scores were more sensitive to immunotherapy. Drug susceptibility analysis revealed differences in the responses to general drugs (docetaxel, cyclophosphamide, 5-Fluorouracil, cisplatin, paclitaxel, and vincristine) were yielded between the two risk groups.ConclusionIdentifying the SRG-score signature may become a promising method for predicting the prognosis of patients with PCa and tailoring appropriate treatment strategies.

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“…The reconstruction of transcriptional regulatory networks based on regulatory hubs is a successful approach to investigating cancer biological mechanisms and elucidating drivers of tumor behavior 20–25 . This reverse‐engineering method is based on mutual information and can identify key regulatory elements that trigger a phenotype 26,27 .…”

Section: Introductionmentioning

confidence: 99%

Revealing metastatic castration‐resistant prostate cancer master regulator through lncRNAs‐centered regulatory network

Ferraz,

Cavalcante,

Magalhães

et al. 2023

Cancer Medicine

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BackgroundMetastatic castration‐resistant prostate cancer (mCRPC) is an aggressive form of cancer unresponsive to androgen deprivation therapy (ADT) that spreads quickly to other organs. Despite reduced androgen levels after ADT, mCRPC development and lethality continues to be conducted by the androgen receptor (AR) axis. The maintenance of AR signaling in mCRPC is a result of AR alterations, androgen intratumoral production, and the action of regulatory elements, such as noncoding RNAs (ncRNAs). ncRNAs are key elements in cancer signaling, acting in tumor growth, metabolic reprogramming, and tumor progression. In prostate cancer (PCa), the ncRNAs have been reported to be associated with AR expression, PCa proliferation, and castration resistance. In this study, we aimed to reconstruct the lncRNA‐centered regulatory network of mCRPC and identify the lncRNAs which act as master regulators (MRs).MethodsWe used publicly available RNA‐sequencing to infer the regulatory network of lncRNAs in mCRPC. Five gene signatures were employed to conduct the master regulator analysis. Inferred MRs were then subjected to functional enrichment and symbolic regression modeling. The latter approach was applied to identify the lncRNAs with greater predictive capacity and potential as a biomarker in mCRPC.ResultsWe identified 31 lncRNAs involved in cellular proliferation, tumor metabolism, and invasion‐metastasis cascade. SNHG18 and HELLPAR were the highlights of our results. SNHG18 was downregulated in mCRPC and enriched to metastasis signatures. It accurately distinguished both mCRPC and primary CRPC from normal tissue and was associated with epithelial–mesenchymal transition (EMT) and cell‐matrix adhesion pathways. HELLPAR consistently distinguished mCRPC from primary CRPC and normal tissue using only its expression.ConclusionOur results contribute to understanding the regulatory behavior of lncRNAs in mCRPC and indicate SNHG18 and HELLPAR as master regulators and potential new diagnostic targets in this tumor.

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Comprehensive Characterization of the Regulatory Landscape of Adrenocortical Carcinoma: Novel Transcription Factors and Targets Associated with Prognosis

Cited by 5 publications

References 81 publications

Steroidogenic Factor 1, a Goldilocks Transcription Factor from Adrenocortical Organogenesis to Malignancy

Steroidogenic Factor 1, a Goldilocks Transcription Factor from Adrenocortical Organogenesis to Malignancy

Identification of a novel senescence-associated signature to predict biochemical recurrence and immune microenvironment for prostate cancer

Revealing metastatic castration‐resistant prostate cancer master regulator through lncRNAs‐centered regulatory network

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