MPP7 inhibits tumor metastasis through promoting snail degradation in clear cell renal cell carcinoma.

BACKGROUND: Tumor metastasis is a major factor of high recurrence and mortality in clear cell renal cell carcinoma (ccRCC), but its underlying mechanism remains elusive. This study focuses on investigating the impact and underlying molecular mechanisms of MAGUK p55 subfamily member 7 (MPP7) on the metastasis of ccRCC. METHODS: The clinical significance of MPP7 in patients with ccRCC was investigated based on The Cancer Genome Atlas (TCGA), Genotype Tissue Expression Project (GTEx) databases and clinical tissue samples. Slow aggregation, microscopic photography and immunofluorescence (IF) assay were applied to assess the effect of MPP7 on intercellular adhesion, cell morphology, and cytoskeletal F-actin, respectively. Transwell and wound-healing assays were used to detect cell migration and invasion. The quantitative real-time polymerase chain reaction (qRT-PCR), western blot, IF, co-immunoprecipitation (Co-IP), and immunoprecipitation-mass spectrometry (IP-MS) were applied to elucidate the underlying molecular mechanism. RESULTS: High expression of MPP7 in ccRCC was associated with a better prognosis. Biologically, MPP7 increased intercellular adhesion, affected cell morphology, prevented the overgrowth of F-actin, and significantly inhibited the metastasis of ccRCC cells both in vitro and in vivo. Mechanistically, MPP7 competed with F-actin to bind to α-actinin-4 (ACTN4) through its GuK domain, thereby inhibiting F-actin polymerization. The reduced F-actin aggregation decreased the spatial sequestration of the E3 ligase tripartite motif-containing protein 21 (TRIM21), thus strengthening its access to Snail. The enhanced interaction between TRIM21 and Snail promoted the ubiquitin-proteasome-mediated degradation of Snail, ultimately leading to decreased migration and invasion abilities. CONCLUSIONS: Our work elucidated the role and molecular mechanism of MPP7 in migration and invasion regulation of ccRCC.