# miR‐221/222 Facilitate Pituitary Adenoma Progression Via PHACTR4 Downregulation

## TL;DR

This study shows that miR-221/222 promotes pituitary tumor growth by reducing PHACTR4 levels, offering a new target for diagnosis and treatment.

## Contribution

Identifies miR-221/222 as a proto-oncogene in pituitary adenomas through PHACTR4 downregulation.

## Key findings

- miR-221/222 expression is elevated in plasma exosomes of pituitary tumor patients.
- PHACTR4 is a direct target of miR-221/222, and its overexpression reverses miR-221/222 effects.
- miR-221/222 promotes tumor growth in vivo by targeting PHACTR4.

## Abstract

Most of pituitary adenomas are biologically benign, but some grow local‐invasively and can invade important adjacent tissues, resulting in clinical symptoms such as hormone secretion disorders and visual field defects. MicroRNA‐221/222 (miR‐221/222) is tandemly encoded on the X chromosome in humans, mice and rats, and is highly conserved in vertebrates with the same seed sequence. To date, miR‐221/222 has been reported as either a tumor suppressor or a tumor promoter in different tumors, however, its role in pituitary tumors has not been elucidated. Our study aimed to investigate the effect and mechanism of miRNA‐221/222 in pituitary tumor cells. Results of real‐time quantitative PCR showed that the expression level of miRNA‐221/222 in plasma exosomes from patients with pituitary tumor was significantly higher than that from healthy people. Results of cell function experiments indicated that miRNA‐221/222 significantly promoted cell proliferation and migration, inhibited apoptosis and significantly inhibited the expression of Cleaved‐Caspase3 and E‐cadherin, while promoted the expression level of N‐cadherin. With transcriptome sequencing and comprehensive bioinformatics analysis, PHACTR4 was identified as the potential target gene of miRNA‐221/222 in regulating biological functions of pituitary adenoma cells. Dual luciferase reporter assay confirmed that PHACTR4 was the direct target gene of miRNA‐221/222 and overexpression of PHACTR4 gene reversed the regulatory effects of miRNA‐221/222. In vivo experiment of subcutaneous tumor formation in nude mice verified that miRNA‐221/222 promoted tumor growth by targeting PHACTR4. In conclusion, miRNA‐221/222 played the role of proto‐oncogene in the occurrence and development of pituitary tumors by targeting PHACTR4, which provided a new target for the diagnosis and molecular treatment of pituitary adenomas.