Capn4, a small regulatory subunit of the calpain proteolytic system, functions as a potential tumor promoter in several cancers. However, the biological functions and molecular mechanisms of Capn4 in gastric cancer (GC) remain poorly understood. In the current study, we found that upregulation of Capn4 was detected frequently in GC tissues, and was associated with significantly worse survival among the GC patients. Multivariate analyses revealed that abundance of Capn4 was an independent predictive marker for the poor prognosis of GC. Further, Capn4 knockdown notably suppressed GC invasion and metastasis in vitro. Consistently, a xenograft assay showed that silencing of Capn4 in GC cells suppressed their dissemination to lung tissue in vivo. Moreover, our results indicated that Capn4 promotes gastric cancer metastasis by increasing MMP9 expression, and demonstrated that MMP9 is crucial for the pro-metastasis role of Capn4 in GC cells. Further investigation revealed that Capn4 regulated MMP9 expression via activation of Wnt/β-catenin signaling pathway. Mechanistically, we found that Capn4 can decreased β-catenin ubiquitination to enhance the protein stability of β-catenin in GC cells. Collectively, Capn4 has a central role in gastric cancer metastasis, which could be a potential diagnostic and therapeutic target for GC.
Keywords: Capn4; Gastric cancer; MMP9; Ubiquitination; β-Catenin.
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