MicroRNA‑199a‑3p suppresses non‑small cell lung cancer progression by targeting FTO to enhance m6A‑mediated downregulation of MZF1 and its transcriptional activation of CLDND1.

The present study aimed to investigate the effect of microRNA (miR)-199a-3p on the biological function of non-small cell lung cancer (NSCLC) adenocarcinoma cells by targeting the fat mass and obesity‑associated protein (FTO)/myeloid zinc finger 1 (MZF1)/claudin domain‑containing 1 (CLDND1) axis. Human NSCLC cell lines, primarily A549 cells, were used for in vitro assays. Reverse transcription‑quantitative PCR and western blotting were performed to assess the expression of relevant genes and proteins. Dual‑luciferase reporter assays were used to verify the relationship between miR‑199a‑3p and FTO, as well as the transcriptional regulation of CLDND1 by MZF1. Methylated RNA immunoprecipitation was used to evaluate the N(6)‑methyladenosine (m(6)A) modification levels of MZF1, whereas photoactivatable ribonucleoside‑enhanced crosslinking and immunoprecipitation supported the binding of FTO to MZF1 mRNA. Cell proliferation, migration, invasion and apoptosis were assessed using Cell Counting Kit‑8, Transwell and flow cytometry assays. miR‑199a‑3p was downregulated in NSCLC tissues and cells. Overexpression of miR‑199a‑3p inhibited A549 cell proliferation, invasion and migration. Mechanistically, miR‑199a‑3p directly targeted and suppressed FTO, an m6A demethylase, leading to enhanced m(6)A modification of MZF1 mRNA and a subsequent decrease in MZF1 expression. Knockdown of MZF1 attenuated the oncogenic effects mediated by FTO, confirming that MZF1 served as a downstream effector of the miR‑199a‑3p/FTO axis. Moreover, MZF1 transcriptionally activated CLDND1, thereby facilitating the malignant phenotype of NSCLC cells. Collectively, these findings demonstrate that miR‑199a‑3p suppresses NSCLC progression by targeting FTO, promoting m(6)A methylation‑dependent downregulation of MZF1, and consequently decreasing CLDND1 expression. Thus, the miR‑199a‑3p/FTO/MZF1/CLDND1 axis may serve as a promising therapeutic target in NSCLC.