The dual tumor-suppressive mechanisms of STAM in clear cell renal cell carcinoma: EGFR inactivation and autophagy activation via AKT regulation

Clear cell renal cell carcinoma (ccRCC), the most prevalent and aggressive subtype of kidney cancer, is highly resistant to first-line therapy. Our previous studies demonstrated that signal transducing adaptor molecule (STAM) suppressed ccRCC progression, with the MAGI2AS3/miR-142-3p/STAM axis acting as an upstream regulator of STAM in the suppression of ccRCC. However, the precise tumor-suppressive mechanism of STAM in ccRCC remains poorly understood. In this study, in vitro and in vivo models were used to investigate the role of STAM in ccRCC suppression. STAM overexpression was induced in ccRCC cell lines (OSRC-2 and ACHN) to evaluate its effect on cell proliferation, migration, and invasion. EGFR endocytosis, autophagy, and key signaling pathways were analyzed using immunofluorescence and western blotting. A subcutaneous xenograft mouse model was used to examine tumor growth. STAM overexpression enhanced EGFR endocytosis and autophagy, leading to inhibition of ccRCC cell proliferation, migration, and invasion. Mechanistically, STAM inactivates EGFR, thereby suppressing the MAPK/ERK signaling pathway. Moreover, STAM reduced AKT mRNA abundance and promoted AKT protein degradation through the ubiquitin–proteasome and autophagy–lysosome pathways. Subcutaneous xenograft models have confirmed that ERK activation or autophagy inhibition reverses STAM-mediated tumor suppression. This study is the first to demonstrate that STAM acts as a critical tumor suppressor in ccRCC through two mechanisms: (1) inactivation of EGFR to suppress MAPK/ERK signaling and (2) reduction of AKT mRNA abundance and promotion of AKT protein degradation to inhibit PI3K/AKT signaling, thus inducing autophagy. These findings support the use of STAM as a promising dual-target therapeutic strategy for ccRCC treatment.