Ring finger protein 125, as a potential highly aggressive and unfavorable prognostic biomarker, promotes the invasion and metastasis of human gallbladder cancers via activating the TGF-β1-SMAD3-ID1 signaling pathway

// Zhong-Yan Liu 1, * , Jin Cao 1, * , Jing-Tao Zhang 1, * , Guo-Li Xu 1 , Xin-Ping Li 1 , Fang-Tao Wang 1 , Kamar Hasan Ansari 1 , Hassan Mohamed 1 and Yue-Zu Fan 1 1 Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200065, P.R. China * These authors have contributed equally to this work Correspondence to: Yue-Zu Fan, email: fanyuezu@hotmail.com Keywords: gallbladder neoplasm, ring finger protein 125, metastasis, prognosis, signaling pathway Received: December 10, 2016 Accepted: April 19, 2017 Published: May 25, 2017 ABSTRACT Human gallbladder cancer (GBC) is a lethal aggressive malignant neoplasm. Identification of potential molecular biomarkers and development of targeted therapeutics for GBC patients is very necessary. In this study, we firstly investigated the correlation between ring finger protein 125 (RNF125) expression and the metastasis and prognosis of GBC, and the underlying molecular mechanism. RNF125 expression in a cohort of GBC tissues was examined; its correlation with clinicopathological and prognostic factors of GBC patients was analyzed. Moreover, the metastasis-related difference expressed genes in highly and lowly aggressive GBC cell lines were identified; and the influence of RNF125 knockdown on the metastatic phenotypes and characteristic EMT markers in highly aggressive GBC NOZ cells was detected. Furthermore, the underlying molecular mechanism of RNF125 effect was explored. The results showed that RNF125 was highly expressed in GBC tissues and related with aggressive characteristics such as Nevin stage ( P = 0.041) etc. and unfavorable prognosis of GBC patients ( P = 0.023, log-rank test). And, RNF125 was proved to a positive metastasis-related gene in vitro . RNF125 knockdown inhibited the invasion and migration, enhanced the adhesion, upregulated E-cadherin and β-catenin expression, and downregulated vimentin and N-cadherin expression (all P < 0.001) of NOZ cells in vitro . RNF125 promoting effect on GBC tumor progression was identified to relate with the activation of TGF-β1-SMAD3-ID1 signaling pathway. These findings firstly confirm that high RNF125 expression is related with aggressive characteristics and unfavorable prognosis of GBC patients; RNF125 promotes the invasion and metastasis of human GBCs via activating the TGF-β1-SMAD3-ID1 signaling pathway.