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.
Highlights
Human gallbladder cancer (GBC), a lethal aggressive malignant neoplasm, is the most common malignancy of the biliary tract, the 5th or 6th common malignant neoplasm of the digestive tract and the leading cause of cancer-related deaths in West countries and China [1,2,3,4]
ring finger protein 125 (RNF125) expression was correlated with tumor differentiation (P = 0.017), Nevin stage (P = 0.042), Union for International Cancer Control (UICC) stage (P = 0.021), liver metastasis (P = 0.020) and vascular invasion (P = 0.016), whereas no correlation was observed with gender, age, tumor location, tumor size, histological type, lymph node metastasis and resection type
The univariate analysis indicated that histological type (P = 0.008), tumor differentiation (P = 0.000), Nevin stage (P = 0.003), UICC stage (P = 0.000), liver metastasis (P = 0.015), vascular invasion (P = 0.000), lymph node metastasis (P = 0.000), resection type (P = 0.000) and RNF125 (P = 0.022) were all prognostic factors for overall survival (OS) in GBC patients; but the multivariate analysis confirmed that only tumor differentiation (P = 0.001), Nevin stage (P = 0.041), resection type (P = 0.020) and RNF125 (P = 0.041) were independent prognostic factors for OS in GBC patients (Table 2)
Summary
Human gallbladder cancer (GBC), a lethal aggressive malignant neoplasm, is the most common malignancy of the biliary tract, the 5th or 6th common malignant neoplasm of the digestive tract and the leading cause of cancer-related deaths in West countries and China [1,2,3,4]. Highly aggressive GBC is a considerable clinical problem due to diagnostic delay, dismal results of surgical resection and chemoradiotherapy for the disease, and due to the complexity of targeting the elusive metastatic phenotypes [4, 5]. Identification of special biological behaviors, further understanding the mechanism of metastasis and www.impactjournals.com/oncotarget development of potential targeted interventions for GBCs is of very significant, and remain challenging [4,5,6,7]. Recent developments in molecular biomarkers, targeted therapeutics, directed against key signal pathways in GBCs appear promising [4, 5, 8,9,10,11,12]. Specific molecular biomarkers for invasion and metastasis of GBC, which can predict the patient prognosis and the response of targeted therapeutic, are very few and not thoroughly elucidated
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