Evidence for a Tumor-Suppressive Role of SHP-1 in EMT Regulation in Bladder Cancer Cells

Background/Objectives: Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1), also known as protein tyrosine phosphatase non-receptor type 6, functions as a tumor suppressor in breast, hepatocellular, and prostate cancers and an oncogene in glioblastoma and cervical cancer. A previous analysis of The Cancer Genome Atlas (TCGA) dataset revealed that lower SHP-1 transcript levels in bladder tumors were associated with poorer overall survival. Methods: This study aimed to evaluate the role of SHP-1 in bladder cancer and to assess the functional impact of its forced expression and knockdown in bladder carcinoma cell lines. SHP-1 expression was assessed in 19 bladder cancer cell lines and 26 bladder tissues. Lentiviral transduction was used to knock down or overexpress SHP-1 in four cell lines, followed by Western blot analysis of SHP-1 and pAkt/Akt protein expression. Results: SHP-1 protein levels were significantly lower in highly invasive cell lines (p < 0.001) and muscle-invasive tumors (p < 0.05). Functional studies demonstrated that SHP-1 modulation influenced the epithelial-mesenchymal transition (EMT) phenotype. SHP-1 expression was positively correlated with E-cadherin expression (p < 0.001) and negatively correlated with N-cadherin (p < 0.01) and Vimentin (p < 0.05) expression. Alteration of SHP-1 expression in bladder cancer cell lines affected proliferation, invasion, and migration (p < 0.05). RNA-seq analysis of the transduced cell lines revealed enrichment of gene sets related to EMT and signaling pathways involving MYC, PI3K, Akt, and mTOR. Furthermore, SHP-1 alteration impacted pAkt/Akt ratios (p < 0.05). Conclusions: Collectively, lower SHP-1 protein expression correlated with more aggressive phenotypes in bladder cancer cell lines and bladder tumors. In our limited dataset, reduced SHP-1 expression correlated with muscle-invasive disease, suggesting a potential link to more advanced tumor biology, consistent with TCGA associating reduced SHP-1 transcript expression to poorer survival rates. Our data provide preliminary functional evidence that SHP-1 may modulate Akt signaling in bladder cancer. Together, these results support further investigation of SHP-1 as a possible tumor suppressor, candidate prognostic biomarker, and potential therapeutic target in bladder cancer.