Widespread peritoneal metastasis is a key reason for high mortality in ovarian cancer and understanding its mechanisms will offer new targets for the effective treatment of metastatic ovarian cancer. Our previous research revealed that collagen type I alpha 1 (COL1A1)-induced upregulation of lysyl oxidase-like 2 (LOXL2) was markedly overexpressed in ovarian cancer tissue samples and ascites. LOXL2 serves as an independent risk factor for predicting prognosis and its high expression is associated with high-risk clinical factors. LOXL2 promoted migration and invasion of ovarian cancer cells and metastasis of transplanted tumors in the xenograft mouse model. Here we determined that, mechanistically, COL1A1 activated the EGFR-MEK-ERK signaling pathway, which subsequently facilitated the nuclear translocation of SP1. SP1 binds to the promoter region of LOXL2, augmenting its transcription. Meanwhile, LOXL2 interacts with EGFR, protecting it from lysosomal degradation and enhancing protein stability. Finally, EGFR activates the MEK-ERK signaling pathway, promoting the translocation of SP1 and forming positive feedback. Our findings confirmed the molecular mechanism by which COL1A1-induced upregulation of LOXL2 promotes ovarian cancer metastasis through a positive feedback loop involving EGFR-MEK-ERK-SP1, offering novel scientific insights and potential therapeutic targets for inhibiting ovarian cancer metastasis.
Shen et al. (Wed,) studied this question.