<scp>CircRAPGEF5</scp> Promotes <scp>LUAD</scp> by Mediating the <scp>HOXC6</scp> Stability

Lung adenocarcinoma (LUAD) is the fifth leading cause of cancer-related deaths worldwide. Due to nonspecific early symptoms, most patients with LUAD are diagnosed at advanced stages, marked by extensive metastases and a poor 5-year survival rate. Although HOXC6 has been implicated in promoting LUAD tumorigenesis, its upstream and downstream mechanisms remain largely unknown. This study aimed to elucidate the role and molecular mechanisms of HOXC6 in LUAD progression. RT-qPCR, IHC, western blot, and IF staining assays were used to assess the expression levels of genes and proteins. Proliferation, migration, and invasion were evaluated using the CCK-8, scratch, and Transwell assays, respectively. ChIP, RIP, and dual-luciferase assays were performed to explore the interactions among HOXC6, HOXB2, circRAPGEF5, and HNRNPC. Additionally, in vivo xenograft and metastatic mouse models were established. FISH was used to detect circRAPGEF5 expression in LUAD tissues. circRAPGEF5 knockdown inhibited LUAD cell proliferation, migration, and invasion as well as tumor growth and metastasis in vivo. Mechanistically, circRAPGEF5 enhanced the stability of HOXC6 mRNA by interacting with HNRNPC, thereby promoting HOXC6 expression. HOXC6 transcriptionally activated HOXB2. Notably, HOXC6 overexpression counteracted the inhibitory effects of circRAPGEF5 knockdown on LUAD progression. Collectively, our findings indicated that circRAPGEF5 facilitates LUAD progression and metastasis by stabilizing HOXC6 mRNA via HNRNPC and promoting HOXB2 transcription. These results suggest that targeting circRAPGEF5 and HOXC6 can be a promising approach for LUAD treatment.