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The main pathogenesis of the frozen shoulder is thought to be the inflammation of the intra‐articular synovium and subsequent fibrosis of the shoulder joint capsule. However, the molecular pathogenesis of the frozen shoulder is still unknown. A class of noncoding RNAs, microRNAs contribute to various diseases including musculoskeletal diseases. MicroRNA‐26a (miR‐26a) has been reported to be associated with fibrosis in several organs. This study aims to reveal the role of miR‐26a on fibrosis in the shoulder capsule using a frozen shoulder model in miR‐26a deficient (miR‐26a KO) mice. MiR‐26a KO and wild‐type (WT) mice were investigated using a frozen shoulder model. The range of motion (ROM) of the shoulder, histopathological changes such as synovitis, and fibrosis‐related gene expression in the model mice were evaluated to determine the role of miR‐26a. In WT mice, both inflammatory cell infiltration and thickening of the inferior shoulder joint capsule were observed after 1 week of immobilization, and this thickening further progressed over the subsequent 6 weeks. However, the immobilized shoulder in miR‐26a KO mice consistently exhibited significantly better ROM compared with WT mice at 1 and 6 weeks, and histological changes were significantly less severe. The expression of inflammation‐ and fibrosis‐related genes was decreased in the miR‐26a KO mice compared with WT mice at 1 and 6 weeks. Together, miR‐26a deficiency attenuated the severity of frozen shoulder in the immobilization model mouse. The present study suggests that miR‐26a has the potential to be a target miRNA for therapeutic approach to frozen shoulder. [ABSTRACT FROM AUTHOR]

Simple Summary: Here, we examined the functional role of Ezin-radixin-moesin-binding phosphoprotein 50 (EBP50) during colorectal carcinoma (CRC) progression. EBP50 depletion was frequently found in the outer areas of tumor lesions and was significantly associated with several unfavorable prognostic factors including depressive tumor growth, deep invasions, high tumor budding (BD), and the presence of neural invasion in CRC cases. EBP50-knockout CRC cells disrupted the interaction between EBP50 and β-catenin at the plasma membrane, leading to epithelial–mesenchymal transition (EMT)-like features, decreased proliferation, accelerated migration capability, and stabilized nuclear β-catenin. In addition, Slug expression was positively correlated with nuclear β-catenin status in tumor outer lesions including BD areas, consistent with β-catenin-driven transactivation of the Slug promoter. These findings suggest that EBP50 depletion is due to nuclear β-catenin accumulation, allowing transactivation of the Slug gene to promote EMT. This in turn contributes to the progression of CRC to a more aggressive phase through the induction of tumor budding. Ezin-radixin-moesin-binding phosphoprotein 50 (EBP50) is a scaffold protein that interacts with several partner molecules including β-catenin. Here, we examined the crosstalk between EBP50 and nuclear catenin during colorectal carcinoma (CRC) progression. In clinical samples, there were no correlations between the subcellular location of EBP50 and any clinicopathological factors. However, EBP50 expression was significantly lower specifically in the outer areas of tumor lesions, in regions where tumor budding (BD) was observed. Low EBP50 expression was also significantly associated with several unfavorable prognostic factors, suggesting that EBP50 depletion rather than its overexpression or subcellular distribution plays an important role in CRC progression. In CRC cell lines, knockout of EBP50 induced epithelial–mesenchymal transition (EMT)-like features, decreased proliferation, accelerated migration capability, and stabilized nuclear β-catenin due to disruption of the interaction between EBP50 and β-catenin at the plasma membrane. In addition, Slug expression was significantly higher in outer lesions, particularly in BD areas, and was positively correlated with nuclear β-catenin status, consistent with β-catenin-driven transactivation of the Slug promoter. Together, our data suggest that EBP50 depletion releases β-catenin from the plasma membrane in outer tumor lesions, allowing β-catenin to accumulate and translocate to the nucleus, where it transactivates the Slug gene to promote EMT. This in turn triggers tumor budding and contributes to the progression of CRC to a more aggressive phase. [ABSTRACT FROM AUTHOR]