Abstract
BackgroundAccumulating evidence has indicated that long non-coding RNAs (lncRNAs) behave as a novel class of transcription products during multiple cancer processes. However, the mechanisms responsible for their alteration in cholangiocarcinoma (CCA) are not fully understood.MethodsThe expression of SPRY4-IT1 in CCA tissues and cell lines was determined by RT-qPCR, and the association between SPRY4-IT1 transcription and clinicopathologic features was analyzed. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to explore whether SP1 could bind to the promoter region of SPRY4-IT1 and activate its transcription. The biological function of SPRY4-IT1 in CCA cells was evaluated both in vitro and in vivo. ChIP, RNA binding protein immunoprecipitation (RIP) and luciferase reporter assays were performed to determine the molecular mechanism of SPRY4-IT1 in cell proliferation, apoptosis and invasion.ResultsSPRY4-IT1 was abnormally upregulated in CCA tissues and cells, and this upregulation was correlated with tumor stage and tumor node metastasis (TNM) stage in CCA patients. SPRY4-IT1 overexpression was also an unfavorable prognostic factor for patients with CCA. Additionally, SP1 could bind directly to the SPRY4-IT1 promoter region and activate its transcription. Furthermore, SPRY4-IT1 silencing caused tumor suppressive effects via reducing cell proliferation, migration and invasion; inducing cell apoptosis and reversing the epithelial-to-mesenchymal transition (EMT) process in CCA cells. Mechanistically, enhancer of zeste homolog 2 (EZH2) along with the lysine specific demethylase 1 (LSD1) or DNA methyltransferase 1 (DNMT1) were recruited by SPRY4-IT1, which functioned as a scaffold. Importantly, SPRY4-IT1 positively regulated the expression of EZH2 through sponging miR-101-3p.ConclusionsOur data illustrate how SPRY4-IT1 plays an oncogenic role in CCA and may offer a potential therapeutic target for treating CCA.
Highlights
Accumulating evidence has indicated that long non-coding RNAs behave as a novel class of transcription products during multiple cancer processes
The results demonstrated that SPRY4-IT1 was dramatically increased in CCA samples compared with those in the normal counterparts (Fig. 1a)
Kaplan-Meier analyses and log-rank tests showed that higher SPRY4-IT1 expression levels indicated worse progression free survival (PFS) and overall survival (OS) after radical surgery in patients with CCA (Fig. 1c and d)
Summary
Accumulating evidence has indicated that long non-coding RNAs (lncRNAs) behave as a novel class of transcription products during multiple cancer processes. The mechanisms responsible for their alteration in cholangiocarcinoma (CCA) are not fully understood. Cholangiocarcinoma (CCA) is a highly aggressive neoplasm that originates from cholangiocytes and has increasing incidence and prevalence rates [1]. There is no effective chemoprevention or radiotherapy for CCA [2]. Despite advances in surgical techniques and an improved understanding of the role of vascular resection and reconstruction, the 5-year survival rates after radical surgery range from 15% to 35% for CCA [4]. CCA is a complex biological process that results from the dysregulation of many cancer-related genes.
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