HOXC8 derived from cancer-associated fibroblasts regulates lung cancer cell malignant metastasis and ferroptosis by mediating the transcription of GCH1.

BACKGROUND

In the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play a role in aggravating the tumor progression. However, research on its specific mechanisms of action remains insufficient. The aim of this study was to clarify the role of the transcription factor homeobox C8 (HOXC8) in CAFs and GTP cyclohydrolase I (GCH1) in the lung cancer.

METHODS

MTT, EdU, Transwell, and stemness assays were employed to measure the biological behaviors of lung cancer cells. The ferroptosis-related indicators were determined by corresponding kits. The GEO database and TGCA samples were used to analyze the differentially expressed genes of CAFs after co-culture with lung cancer cells and the expression of HOXC8 in lung adenocarcinoma. Bioinformatics analysis and dual luciferase reporter system were used to detect the interaction between HOXC8 and GCH1. A xenograft tumor model and IHC staining were used to determine the effect of CAFs on tumor growth and GCH1 expression in vivo.

RESULTS

CAFs accelerated lung cancer cell viability, proliferation, metastasis, sphere formation efficiency, and blocked ferroptosis-related indicators, but upregulated the HOXC8 level. The si-HOXC8-CAFs restrained the malignant progression of lung cancer cells. Interestingly, it was proved that HOXC8 bound to the promoter of GCH1 and induced its expression. Besides, overexpression of GCH1 rescued the effect of CAFs with knockdown of HOXC8 on lung cancer cells. CAFs with silenced HOXC8 inhibited tumor growth and GCH1 expression in vivo.

CONCLUSION

Our results indicate that CAFs-derived exosomes are a key source of HOXC8 in lung cancer cells. HOXC8 directly binds to the GCH1 promoter to activate its transcription, which in turn suppresses ferroptosis and promotes lung cancer progression. These findings contribute to the new intervention and treatment options for combating the malignant progression of lung cancer.