ERRα promotes gallbladder cancer development by enhancing the transcription of Nectin‐4

Estrogen-related receptor-alpha (ERRalpha) is a nuclear receptor of transcription factor that binds to estrogen responsive elements and estrogen-related responsive elements. Estrogen-related receptor-alpha is involved in metabolic processes and implicated in the progression and growth of several human malignancies. However, the biologic role and clinical significance of ERRalpha in gallbladder cancer (GBC) remains to be clarified. Here, we reported that ERRalpha protein expression was notably higher in GBC tissues than in cholecystitis tissues, and that the aberrantly higher ERRalpha 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 ERRalpha 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, ERRalpha knockdown inhibited tumor growth in nude mice and led to decreased expression levels of Nectin-4, p-PI3K p85alpha, and p-AKT. Overexpression of ERRalpha 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 ERRalpha upregulation. Moreover, Nectin-4 depletion inhibited the ERRalpha-induced activation of the PI3K/AKT pathway. Chromatin immunoprecipitation analysis and dual-luciferase reporter gene assays showed that ERRalpha enhanced the transcription of Nectin-4 by binding to the promoter of Nectin-4. In conclusion, our data indicated that ERRalpha could be a potential target for the genetic treatment of GBC.