MiR-181a Targets PHLPP2 to Augment AKT Signaling and Regulate Proliferation and Apoptosis in Human Keloid Fibroblasts

Abstract

Background/Aims: Keloids are fibrous overgrowths induced by cutaneous injury. MicroRNAs (miRNAs) have recently emerged as post-transcriptional gene repressors and participants in a diverse array of pathophysiological processes leading to skin disease. The purpose of the current study was to explore the precise functions of miR-181a in human keloid development and the underlying mechanisms. Methods: A miRNA microarray analysis was performed to compare expression profiles between keloid and normal skin tissues. Quantitative real-time PCR was conducted to estimate miR-181a expression. Cell proliferation was determined using the cell counting kit-8 (CCK-8) and 5-ethynyl-2-deoxyuridine (EdU) assays, and cell cycle and apoptosis were detected with flow cytometry. Direct targets of miR-181a were identified using the luciferase reporter assay. Results: miR-181a was significantly upregulated in human keloid tissues and fibroblasts, compared with their control counterparts. Overexpression of miR-181a enhanced keloid fibroblast DNA synthesis and proliferation and inhibited apoptosis, whereas miR-181a suppression triggered the opposite effects. Moreover, miR-181a suppressed the expression of PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) through direct interactions with its 3′UTR region and subsequently enhanced AKT activation. Overexpression of PHLPP2 without its 3′UTR attenuated the effects of miR-181a on cell proliferation and apoptosis in keloid fibroblast cells. Furthermore, miR-181a mimics increased normal skin fibroblast proliferation. Conclusions: Our results highlight a novel pathway mediated by miR-181a, which may be effectively used as a therapeutic target for treatment of keloids.

Identification and integrated analysis of microRNA expression profiles in keloid

“…miRNA may play a crucial role in the pathogenesis of keloid . The miRNA expression profiles in keloid scarring have been investigated by previous studies.…”

“…Certain miRNAs have been considered to be common regulators in keloid via their relevant target genes . The expression level of miRNA‐199a was lower in the keloid tissue compared to the normal sample.…”

The Dual Regulatory Role of MiR-181a in Breast Cancer

“…Human miR-181a and miR-181b genes are clustered together and located on two chromosomes, 1 and 9, whereas miR-181c and miR-181d genes are clustered together on chromosome 19 [8, 9]. Recent studies have reported the involvement of miR-181a in diverse cellular functions such as growth, proliferation, death, survival, and maintenance, as well as tumor suppression and carcinogenesis [10, 11]. Though some studies have shown that miR-181a expression is downregulated in several human solid tumors [12-17], others have demonstrated that upregulation of miR-181a may promote metastasis and invasion of human cancers [18-20].…”

Expression Profiles of microRNAs in Drug-Resistant Non-Small Cell Lung Cancer Cell Lines Using microRNA Sequencing

“…MicroRNAs (miRNAs), a class of non-coding RNAs with approximately 18-25 nucleotides, are involved in various aspects of cellular functions such as cell proliferation, differentiation, migration, and apoptosis [4][5][6]. Increasing evidence has shown that miRNAs play a vital role in drug resistance [7,8], which leads to treatment failure in cancer.…”