LncRNA MALAT1 Targets METTL3 to Orchestrate INPP5B / LRIG2 Signali

ABSTRACT

m ⁶ A modification regulates the functions of long non‐coding RNAs (lncRNAs) through diverse mechanisms. However, whether the lncRNA MALAT1 regulates the progression of non‐small cell lung cancer (NSCLC) through targeted regulation of METTL3 remains unclear, and the underlying molecular mechanisms have yet to be elucidated. This study aimed to investigate the role of MALAT1 in NSCLC progression by targeting and regulating METTL3. NCI‐H226 NSCLC cells were used as experimental models. RIP and FISH assays were performed to validate the physical interaction between MALAT1 and METTL3. Cells were co‐transfected with si‐MALAT1 and METTL3 overexpression constructs for rescue experiments. FISH was used to determine the subcellular localization of MALAT1. Apoptotic activity was quantified by flow cytometry, while cell proliferation was assessed using the EdU incorporation assay. The Transwell assay was performed to evaluate cell migration, and the EpiQuik m ⁶ A RNA Methylation Quantification Kit was used to detect cellular m ⁶ A methylation levels. Xenograft mouse models were established to evaluate in vivo tumor growth, and clinical NSCLC specimens were analyzed to investigate the clinical correlation among METTL3, INPP5B, and LRIG2. The experimental results showed that MALAT1 was predominantly localized in the nucleus and interacted with METTL3. Following si‐MALAT1 treatment, cell proliferation and migration were decreased, although no significant change was observed in colony formation ability. Furthermore, apoptosis was increased, accompanied by cell cycle arrest at the G0/G1 phase. After MALAT1 interference, transfection with a METTL3 overexpression vector reversed these malignant phenotypes, reduced apoptosis, induced S‐phase accumulation, and significantly downregulated the tumor suppressor gene INPP5B while upregulating the oncoprotein LRIG2. Consistently, in vivo xenograft assays demonstrated that MALAT1 knockdown suppressed tumor growth, which was rescued by METTL3 overexpression. Clinical sample analysis further supported the correlation among METTL3, INPP5B, and LRIG2 in NSCLC tissues. These findings substantiate the regulatory role of MALAT1‐mediated METTL3 modulation in NSCLC progression through the INPP5B/LRIG2 signaling axis.