HMMR is a downstream target of FOXM1 in enhancing proliferation and partial epithelial-to-mesenchymal transition of bladder cancer cells.

Our previous that HMMR upregulation independently predicts poor survival in patients with papillary muscle-invasive bladder cancer (MIBC). In this study, we explored its downstream regulations and the potential transcriptional factors activating its expression. MIBC derived T24 cells, and non-MIBC (NMIBC) derived RT4 cells were used for in vitro and in vivo studies. HMMR expression enhanced cell proliferation, the expression of mesenchymal markers, and cell invasion. It induced the nuclear entry of ß-catenin, increased its active form in the nuclear part, and elevated the relative TOP/FOP activity. The promoter region of HMMR has a canonical FKH motif. FOXM1 bound to this site and activated HMMR transcription. HMMR knockdown significantly weakened FOXM1 overexpression induced bladder cancer growth, invasion, partial epithelial-to-mesenchymal transition (pEMT), as well as the activation of the Wnt/ß-catenin signaling pathway. In conclusion, the findings in this study expanded our understanding of the mechanisms underlying HMMR dysregulation and the functional role of the FOXM1-HMMR axis in bladder cancer.