Identification of tumor-promoting functions of the Homeobox family transcription factor MSX1 in cervical cancer

Cervical cancer (CC) remains a leading cause of cancer-related mortality among women, particularly in underdeveloped or developing countries lacking adequate screening programs. Despite being highly preventable through HPV vaccinations and screening tests, and highly treatable when detected early, CC continues to pose a significant health burden. MSX1, a transcription factor of the homeobox family, plays an important role in the development and differentiation of tissues, including the gynecological tract. Since MSX1 has been identified as both a tumor suppressor and an oncogene in tumorigenesis, but its function in CC remains elusive to date, the present study aims to elucidate the role of MSX1 in CC and its precancerous stages. Our results demonstrate that MSX1 acts as a tumor-promoting factor in CC. While normal squamous epithelium of the cervix is negative for MSX1, we observed de novo expression of MSX1 in precancerous lesions. We found that MSX1 expression enhances the clonogenic and migratory capacities of cervical cancer cell lines. Mechanistic insights revealed an MSX1-dependent induction of the epithelial-to-mesenchymal transition (EMT), a process highly correlated with cancer development and progression. CUT&RUN sequencing data identified enriched signaling of the cytoskeletal modulators RHO/RAC/CDC42 in MSX1-expressing cells, potentially mediated by MSX1. Additionally, FOS, a downstream effector of RHO, was found as a key factor contributing to CC aggressiveness. Interference with both RHO-signaling and FOS-mediated regulation completely reversed the aggressive phenotype of MSX1-expressing cells. In conclusion, our findings suggest that MSX1 plays a crucial role in cancer-related signaling pathways and may have implications for the development of therapeutic approaches in cervical cancer.