Estrogen-related receptor-α promotes gallbladder cancer development by enhancing the transcription of Nectin-4

Estrogen-related receptor-α (ERRα) is a nuclear receptor of transcription factor that binds to estrogen responsive elements and estrogen-related responsive elements. Estrogen-related receptor-α is involved in metabolic processes and implicated in the progression and growth of several human malignancies. However, the biologic role and clinical significance of ERRα in gallbladder cancer (GBC) remains to be clarified. Here, we reported that ERRα protein expression was notably higher in GBC tissues than in cholecystitis tissues, and that the aberrantly higher ERRα expression was positively correlated with advanced TNM stage and indicated dismal prognosis of GBC (P < .01). In GBC cell lines NOZ and OCUG, the targeted depletion of ERRα retarded the growth and suppressed the migration and invasive capabilities of GBC cells, and inhibited epithelial-mesenchymal transition by decreasing the expression of mesenchymal markers and elevating the expression of epithelial markers. Moreover, ERRα knockdown inhibited tumor growth in nude mice and led to decreased expression levels of Nectin-4, p-PI3K p85α, and p-AKT. Overexpression of ERRα in the GBC-SD cell line showed exactly the opposite effect. The targeted inhibition of Nectin-4 antagonized GBC cell proliferation and invasion, which were induced by ERRα upregulation. Moreover, Nectin-4 depletion inhibited the ERRα-induced activation of the PI3K/AKT pathway. Chromatin immunoprecipitation analysis and dual-luciferase reporter gene assays showed that ERRα enhanced the transcription of Nectin-4 by binding to the promoter of Nectin-4. In conclusion, our data indicated that ERRα could be a potential target for the genetic treatment of GBC.