LncRNA MALAT1 Promotes Non-Small Cell Lung Cancer Progression by Regulating FUT4 Expression and EGFR Glycosylation via the PI3K/Akt Pathway

Abstract

Introduction: Lung cancer remains a leading cause of global cancer-related mortality, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Despite advances in surgery, chemotherapy, and immunotherapy, the molecular drivers of metastasis are still poorly understood. This study investigates the oncogenic role of the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and its regulation of fucosyltransferase 4 (FUT4) in NSCLC progression.

Materials and Methods: Expression levels of MALAT1 and FUT4 were analyzed in 19 pairs of NSCLC tissues and 50 serum samples (15 healthy controls, 20 treatment-naïve patients, and 15 post-chemotherapy patients) using quantitative real-time polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). The clinical significance of these markers was evaluated in relation to TNM stage and lymph node metastasis. In vitro functional assays, including Cell Counting Kit-8, colony formation, and Transwell assays, were performed in A549 and H1299 cells following MALAT1 knockdown or FUT4 overexpression. All experiments were conducted in three independent biological replicates. Mechanistic insights were obtained using Western blotting, immunoprecipitation, and lectin blotting to assess epidermal growth factor receptor (EGFR) α1,3-fucosylation and phosphatidylinositol 3-kinase (PI3K)/Akt signaling.

Results: MALAT1 and FUT4 were significantly upregulated in NSCLC tissues and serum compared to controls (P = 0.023 and P = 0.017 for tissue; P = 0.008 and P = 0.011 for serum, respectively). Spearman correlation analysis revealed a significant positive relationship between MALAT1 and FUT4 expression in both tissue (r = 0.509; 95% CI: 0.182–0.742; P = 0.008) and serum samples (r = 0.627; 95% CI: 0.432–0.768; P < 0.001). High expression levels were associated with advanced clinical stage and lymph node metastasis (P = 0.006 and P < 0.001, respectively; these associations should be considered exploratory given the cohort size). Knockdown of MALAT1 significantly inhibited cell proliferation, migration, and invasion (P < 0.01 for all assays). Mechanistically, MALAT1 regulated FUT4 expression – potentially through a microRNA-sponging mechanism (a hypothesis requiring direct experimental validation) which in turn mediated α1,3-fucosylation and Lewis Y biosynthesis on EGFR. Reduced MALAT1 expression led to diminished EGFR activation and subsequent inactivation of the PI3K/ Akt/phosphoinositide-dependent kinase signaling cascade (P < 0.05). FUT4 overexpression partially rescued the malignant phenotype and signaling activity suppressed by MALAT1 silencing (P < 0.05 vs. si-MALAT1 alone), suggesting that additional effectors may contribute to MALAT1-dependent phenotypes.

Conclusions: This study provides evidence that MALAT1 promotes the malignant progression of NSCLC by modulating the FUT4/EGFR/ PI3K/Akt signaling axis. These findings highlight MALAT1 and FUT4 as potential diagnostic biomarkers and therapeutic targets; however, further validation in larger cohorts and in vivo models is required to establish clinical utility and to elucidate the precise regulatory mechanism linking MALAT1 to FUT4 expression.