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

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.

RNF113A promotes the proliferation, migration and invasion, and is associated with a poor prognosis of esophageal squamous cell carcinoma

“…Indeed, RNF183 promotes the proliferation and metastasis of colorectal cancer cells via the activation of the NF-κB-IL-8 axis (45). RNF125 is a potential biomarker for the highly aggressive and unfavorable prognosis of gallbladder cancers by promoting the invasion and metastasis of human gallbladder cancers via the activation of the TGF-β1-SMAD3-ID1 signaling pathway (46). Cancer progression and cell proliferation, migration and invasion are orchestrated by a very complex and interwoven array of molecules.…”

Tenorio syndrome: Description of 14 novel cases and review of the clinical and molecular features

“…Therefore, RNF125 might have an indirect effect on this molecular pathway. Moreover, recent studies have also associated RNF125 expression with the more aggressive forms of gallbladder cancer because it activates the TGF‐β1‐SMAD3‐ID1 signaling pathway 15 …”

RNF125&nbsp;Modulates Tumor Immunity by Promoting Ubiquitination of PD-L1

“…In addition to its role in immune regulation, recent studies have also found that RNF125 is also involved in tumor development and drug resistance [16,17]. However, it is not clear whether RNF125 can modify other substrates through ubiquitination to regulate tumor immunity.…”