Hypoxia-Derived Exosomes Promote Lung Adenocarcinoma by Regulating HS3ST1-GPC4-Mediated Glycolysis

Simple Summary Lung cancer accounts for 11.4% of all cancer cases and 18.0% of all cancer deaths. Understanding the molecular mechanisms underlying lung adenocarcinoma (LUAD), one of the most common lung cancers, is imperative to enhance diagnostic accuracy, drug development, and prognostic evaluation. The present study explored the interaction between heparan sulfate (glucosamine) 3-O-sulfotransferase 1 (HS3ST1) and Glypican 4 (GPC4), as well as the influence of the hypoxia-derived exosomal lncRNA OIP5-AS1 on the glycolysis, proliferation, and metastasis ability in LUAD cell lines and their effects on the tumor growth in xenograft animal models. GPC4 promotes HS3ST1-mediated glycolysis, and the hypoxia-derived exosomal lncRNA OIP5-AS1 promotes glycolysis via the miR-200c-3p axis in LUAD cells. The hypoxia-derived exosomal lncRNA OIP5-AS1 enhances LUAD cell proliferation and metastasis in vitro and promotes LUAD tumor growth and metastasis via miR-200c-3p in vivo. These findings highlight that the hypoxia-derived exosomal lncRNA OIP5-AS1 may participate in LUAD progression.Abstract Objective: The diagnosis of lung adenocarcinoma (LUAD) is often delayed due to the typically asymptomatic nature of the early-stage disease, causing advanced-stage LUAD diagnosis in most patients. Hypoxia is widely recognized as a driving force in cancer progression. Exosomes originating from hypoxic tumor cells promote tumorigenesis by influencing glycolysis, migration, invasion, and immune infiltration. Given these insights, our study aimed to explore the role of hypoxia-derived exosomal long non-coding RNA (lncRNA) OIP5-AS1 in LUAD cell lines and mouse models. Materials and Methods: Exosomes were meticulously isolated and authenticated based on their morphology and biomarkers. The interaction between heparan sulfate (glucosamine) 3-O-sulfotransferase 1 (HS3ST1) and Glypican 4 (GPC4) was examined using immunoprecipitation. The influence of the hypoxia-derived exosomal lncRNA OIP5-AS1 on glycolysis was assessed in LUAD cell lines. The effect of the hypoxia-derived exosomal lncRNA OIP5-AS1 on cell proliferation and metastasis was evaluated using colony formation, cell viability, cell cycle, and apoptosis analyses. Its effects on tumor size were confirmed in xenograft animal models. Results: Our study revealed the mechanism of the hypoxia-derived exosomal lncRNA OIP5-AS1 in LUAD progression. We discovered that GPC4 promotes HS3ST1-mediated glycolysis and that the hypoxia-derived exosomal lncRNA OIP5-AS1 enhances glycolysis by regulating miR-200c-3p in LUAD cells. Notably, this lncRNA stimulates LUAD cell proliferation and metastasis and fosters LUAD tumor size via miR-200c-3p. Our findings underscore the potential role of the hypoxia-derived exosomal lncRNA OIP5-AS1 in LUAD progression. Conclusions: The hypoxia-derived exosomal lncRNA OIP5-AS1 promotes LUAD by regulating HS3ST1-GPC4-mediated glycolysis via miR-200c-3p.