The role of microRNA deregulation in the pathogenesis of adrenocortical carcinoma

Abstract

Adrenocortical carcinoma (ACC) is an aggressive tumor showing frequent metastatic spread and poor survival. Although recent genome-wide studies of ACC have contributed to our understanding of the disease, major challenges remain for both diagnostic and prognostic assessments. The aim of this study was to identify specific microRNAs (miRNAs) associated with malignancy and survival of ACC patients. miRNA expression profiles were determined in a series of ACC, adenoma, and normal cortices using microarray. A subset of miRNAs showed distinct expression patterns in the ACC compared with adrenal cortices and adenomas. Among others, miR-483-3p, miR-483-5p, miR-210, and miR-21 were found overexpressed, while miR-195, miR-497, and miR-1974 were underexpressed in ACC. Inhibition of miR-483-3p or miR-483-5p and overexpression of miR-195 or miR-497 reduced cell proliferation in human NCI-H295R ACC cells. In addition, downregulation of miR-483-3p, but not miR-483-5p, and increased expression of miR-195 or miR-497 led to significant induction of cell death. Protein expression of p53 upregulated modulator of apoptosis (PUMA), a potential target of miR-483-3p, was significantly decreased in ACC, and inversely correlated with miR-483-3p expression. In addition, high expression of miR-503, miR-1202, and miR-1275 were found significantly associated with shorter overall survival among patients with ACC (P values: 0.006, 0.005, and 0.042 respectively). In summary, we identified additional miRNAs associated with ACC, elucidated the functional role of four miRNAs in the pathogenesis of ACC cells, demonstrated the potential involvement of the pro-apoptotic factor PUMA (a miR-483-3p target) in adrenocortical tumors, and found novel miRNAs associated with survival in ACC.

Retracted: MircoRNA‐1275 promotes proliferation, invasion and migration of glioma cells via SERPINE1

“…It has now been clearly established that miRNAs have an important role to regulate the tumorigenesis and metastasis of glioma 21, 22. MiR‐1275 is an intergenic miRNA, which is encoded by chromosome 6 and associated with tumour progression 23. In many researches, miR‐1275 was found to inhibit tumour growth through attenuating relative gene expression.…”

Analysis of circulating microRNAs in adrenocortical tumors

“…18,19 Regarding the significant differences in the expression of tissue miRNAs in ACTs, [13][14][15][16][17] we aimed to investigate their Plasma microRNAs in adrenocortical tumors DR Szabó et al circulating counterparts and to evaluate their potential applicability as biomarkers. The biogenesis and biological relevance of circulating miRNAs are unclear 12 and there are several unresolved issues in their analysis and study design.…”

“…On the basis of the literature search, eight miRNAs reported as significantly differentially expressed between ACA and ACC in tissue miRNA studies have been selected for RT-qPCR analysis (ACA n ¼ 8 and ACC n ¼ 9): hsa-miR-100, 14 hsa-miR181b, 16,17 hsa-miR-184, 17 hsa-miR-195, 14,16 hsa-miR-210, 13,17 hsa-miR-214, 14 hsa-miR-483-5p, 13,14,16 and hsa-miR-503. 17 In contrast with our microarray data, expression of RNU6B seemed to be unstable by RT-qPCR, as in three of eight ACA and in two of nine ACC samples (altogether 29%) no RNU6B signal has been observed.…”

“…12 Numerous studies have shown significantly different tissue miRNA patterns in various neoplasms including ACTs, and some tissue miRNAs can be used for the establishment of malignancy and even as prognostic markers. [13][14][15][16][17] Novel findings revealed that miRNAs can also exist in body fluids and some blood-borne circulating miRNAs have been associated with some diseases including different cancers. 18,19 The source of the circulating miRNAs is unclear, but many miRNAs show the same trend of expression changes in blood samples and tumor tissues of patients with various types of cancer.…”

Tumores adrenocorticais na criança: da abordagem clínica à avaliação molecular

“…Outro estudo recente com TAC em adulto demonstrou 23 miRNAs diferentemente expressos ao comparar adenomas e carcinomas, sendo que a hipoexpressão do miR-195 e hi-perexpressão do miR-483 em carcinomas foi marcador de menor sobrevida (67). Também foi demonstrado papel funcional do miR-483 ao inibir o gene pró-apoptógeno PUMA, favorecendo seu papel na tumorigênese adrenal (68). Mais recentemente, foi avaliada a expressão de miRNA em tumores adrenocorticais pediátricos: miRs-99a e -100 são diferencialmente expressos e podem regular a via do mTOR (alvo da rapamicina em mamífero), o que sugere papel da via e destes miRNAs na tumorigênese adrenal (69).…”