The RNA‐binding protein sorbin and SH3 domain‐containing 2 are transcriptionally regulated by specificity protein 1 and function as tumor suppressors in bladder cancer by stabilizing tissue factor pathway inhibitor

Abstract

AbstractSorbin and SH3 domain‐containing 2 (SORBS2) is an RNA‐binding protein and has been implicated in the development of some cancers. However, its role in bladder cancer (BC) is yet to be established. The expression of SORBS2 in BC tissues was determined from the Gene Expression Omnibus and Gene Expression Profiling Interactive Analysis databases and collected paired tumor/normal samples. The effects of SORBS2 on BC cells were detected by CCK‐8, colony formation, Transwell, dual‐luciferase, RNA immunoprecipitation, chromatin immunoprecipitation, and DNA pull‐down assays. In vivo, BC cell growth and metastasis were studied by a xenograft subcutaneous model and a tail‐vein metastasis model. The results showed that SORBS2 expression was significantly decreased in BC tissues and cells. SORBS2 overexpression inhibited cell proliferation, migration, invasion, and epithelial–mesenchymal transition in vitro and tumor growth and metastasis in vivo, while silencing SORBS2 produced the opposite effect. Mechanistically, we found that SORBS2 enhanced the stability of tissue factor pathway inhibitor (TFPI) mRNA via direct binding to its 3′ UTR. Restoration of TFPI expression reversed SORBS2 knockdown‐induced malignant phenotypes of BC cells. In addition, SORBS2 expression was negatively regulated by the transcription factor specificity protein 1 (SP1). Conversely, SORBS2 can be transcriptionally regulated by SP1 and inhibit BC cell growth and metastasis via stabilization of TFPI mRNA, indicating SORBS2 may be a promising therapeutic target for BC.