HHLA3 Silencing Suppresses KRAS-Mutant Non-Small-Cell Lung Cancer Cell Progression Through Triggering MYEOV-Mediated Ferroptosis

Abstract

KRAS mutation is one of the most common mutational events in non-small-cell lung cancer (NSCLC). However, due to the complex signaling pathways and high biological heterogeneity of KRAS-mutant NSCLC, the current clinical treatment for patients with KRAS mutations still faces many difficulties. The oncogenic effector in KRAS-mutant NSCLC was screened using GEO data sets. CCK-8, colony formation, transwell, and flow cytometry were conducted to assess the malignant phenotype of KRAS-mutant NSCLC cells. The indicators intracellular Fe²⁺, ROS, GSH, and MDA levels were employed to reflect the ferroptosis of cells. The mechanism of myeloma overexpressed (MYEOV) in KRAS-mutant NSCLC was explored from the perspective of noncoding RNA (ncRNA) and validated by rescue experiments. MYEOV presented a high expression trend in KRAS-mutant NSCLC specimens. MYEOV silencing effectively repressed the malignant phenotype and promoted ferroptosis of NSCLC cells carrying KRAS mutations. Based on bioinformation analysis and a series of rescue experiments, we established the HHLA3/miR-139-5p/MYEOV regulatory network in KRAS-mutant NSCLC cells and disclosed that HHLA3 served as a molecular sponge for miR-139-5p to regulate MYEOV expression. The mechanism of MYEOV and its ncRNA network affecting the progression of KRAS-mutant NSCLC revealed in this study intends to provide a theoretical basis for KRAS-mutant NSCLC treatment.