MARCO is associated with radiosensitivity in lung cancer through modulation of Hippo signaling

Lung cancer remains a significant global health challenge, with radiotherapy serving as a cornerstone of treatment. However, the development of resistance to radiation therapy poses a major hurdle in effective disease management. In this study, we explore the novel role of MARCO, a gene involved in antimicrobial defense and cancer progression, in modulating the radiosensitivity of lung cancer cells.Our analysis of clinical samples demonstrated a significant reduction in MARCO expression in lung cancer patients undergoing radiotherapy. In vitro studies using MARCO-overexpressing and MARCO-knockdown lung cancer cells further revealed that MARCO expression was markedly lower in radioresistant lung cancer tissues compared to non-irradiated counterparts. Functionally, overexpression of MARCO enhanced radiosensitivity, whereas its silencing conferred increased resistance to radiation.Mechanistically, MARCO overexpression elevated γ-H2AX levels and suppressed critical DNA repair proteins, including phosphorylated DNA-PK (p-DNA-PK) and RAD51, indicating that both the non-homologous end joining (NHEJ) and homologous recombination (HR) repair pathways were compromised. Furthermore, MARCO overexpression augmented radiation-induced apoptosis-related marker expression, while MARCO silencing diminished these responses. Further investigations identified MARCO as a regulator of the Hippo/YAP signaling pathway. MARCO overexpression inhibited Hippo/YAP signaling and promoted YAP phosphorylation, a key determinant of cell survival and proliferation. In vivo, MARCO silencing resulted in larger tumor volumes and increased Ki67 expression, whereas MARCO overexpression sensitized tumors to radiation and reduced p-YAP levels. Additionally, xenograft models confirmed the radiosensitizing effect of MARCO, as MARCO-knockout tumors exhibited enhanced resistance to radiation therapy, accompanied by increased proliferation and Hippo/YAP pathway activation. These findings establish MARCO as a potential therapeutic target for overcoming radioresistance in lung cancer, offering new insights into strategies to enhance treatment efficacy in patients with advanced disease.