MiR-486-3p was downregulated at microRNA profiling of adrenals of multiple endocrine neoplasia type 1 mice, and inhibited human adrenocortical carcinoma cell lines

Su-Chen Li,Masoud Razmara,Xia Chu,Peter Stålberg,Azita Monazzam,Britt Skogseid

doi:10.1038/s41598-021-94154-z

Su-Chen Li, Masoud Razmara + Show 4 more

Open Access

https://doi.org/10.1038/s41598-021-94154-z

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Journal: Scientific Reports	Publication Date: Jul 20, 2021
Citations: 5	License type: open-access

Affiliation: Uppsala University, Science for Life Laboratory

Abstract

Adrenocortical carcinoma is a rare aggressive disease commonly recurring regardless of radical surgery. Although data on genomic alterations in malignant tumors are accumulating, knowledge of molecular events of importance for initiation of adrenocortical transformation is scarce. In an attempt to recognize early molecular alterations, we used adrenals from young multiple endocrine neoplasia type 1 conventional knock-out mice (Men1+/−) closely mimicking the human MEN1 trait (i.e. transformation of pituitary, parathyroid, endocrine pancreatic, and adrenocortical cells). MicroRNA array and hierarchical clustering showed a distinct pattern. Twenty miRNAs were significantly upregulated and eleven were downregulated in Men1+/− compared to wild type littermates. The latter included the known suppressor miRNA miR-486-3p, which was chosen for transfection in human adrenocortical carcinoma cell lines H295R and SW13. Cell growth decreased in miR-486-3p overexpressing clones and levels of the predicted target gene fatty acid synthase (FASN) and its downstream product, palmitic acid, were lowered. In conclusion, heterozygous inactivation of Men1 in adrenals results in distinct miRNA profile regulating expression of genes with impact on tumorigenesis, e.g. transcription, nucleic acid and lipid metabolism. Low levels of miR-486-3p in the early stages of transformation may contribute to proliferation by increasing FASN and thus fatty acid production. FASN as a potentially druggable target for treatment of the devastating disease adrenocortical carcinoma warrants further studies.

Highlights

Adrenocortical carcinoma is a rare aggressive disease commonly recurring regardless of radical surgery
To enable recognition of early molecular events we chose to study the adrenals of relatively young adult mice, i.e. 10 months old, possibly before long-term proliferation results in further molecular alterations un-related to constitutional heterozygous Men[1] inactivation
The miRNA array profiling, performed on RNA prepared from the adrenal glands of ten Men1+/− and ten wild type (Men+/+) mice revealed a distinct expression pattern

Summary

Introduction

Adrenocortical carcinoma is a rare aggressive disease commonly recurring regardless of radical surgery. In an attempt to recognize early molecular alterations, we used adrenals from young multiple endocrine neoplasia type 1 conventional knock-out mice (Men1+/−) closely mimicking the human MEN1 trait (i.e. transformation of pituitary, parathyroid, endocrine pancreatic, and adrenocortical cells). It has been reported that miRNAs might act either as oncogenes or tumor suppressors during tumorigenesis and progression[19,20] They are important regulators of complex gene networks involved in a variety of biological processes, such as cell proliferation, differentiation, apoptosis, development and metabolism[21,22,23]. As an attempt to recognize potential miRNAs of importance for onset of proliferation in adrenocortical cells, we performed Affymetrix miRNA array from adrenal glands of conventional Men[1] heterozygous knock-out mice (Men1+/−). We used cell lines to study whether one of the differentially regulated miRNAs and its target genes might be of relevance in progression of human adrenocortical carcinoma

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Conclusion