Abstract
Long noncoding RNAs (lncRNAs) emerge as essential roles in the regulation of alternative splicing (AS) in various malignancies. Serine- and arginine-rich splicing factor 1 (SRSF1)-mediated AS events are the most important molecular hallmarks in cancer. Nevertheless, the biological mechanism underlying tumorigenesis of lncRNAs correlated with SRSF1 in esophageal squamous cell carcinoma (ESCC) remains elusive. In this study, we found that lncRNA DiGeorge syndrome critical region gene 5 (DGCR5) was upregulated in ESCC clinical samples, which associated with poor prognosis. Through RNA interference and overexpression approaches, we confirmed that DGCR5 contributed to promote ESCC cell proliferation, migration, and invasion while inhibited apoptosis in vitro. Mechanistically, DGCR5 could directly bind with SRSF1 to increase its stability and thus stimulate alternative splicing events. Furthermore, we clarified that SRSF1 regulated the aberrant splicing of myeloid cell leukemia-1 (Mcl-1) and initiated a significant Mcl-1L (antiapoptotic) isoform switch, which contributed to the expression of the full length of Mcl-1. Moreover, the cell-derived xenograft (CDX) model was validated that DGCR5 could facilitate the tumorigenesis of ESCC in vivo. Collectively, our findings identified that the key biological role of lncRNA DGCR5 in alternative splicing regulation and emphasized DGCR5 as a potential biomarker and therapeutic target for ESCC.
Highlights
Esophageal cancer (EC) is one of the most aggressive cancer worldwide and contributes the sixth highest cancer-related mortality rate[1]
DiGeorge syndrome critical region gene 5 (DGCR5) is upregulated in human esophageal squamous cell carcinoma (ESCC) tissues and DGCR5 overexpression correlates with poor prognosis To investigate the function of Long noncoding RNAs (lncRNAs) DGCR5 in ESCC
We examined the expression of DGCR5 was positively associated with the TNM stage of ESCC, suggesting that higher expression of DGCR5 was significantly correlated with advanced ESCC patients (Fig. 1C)
Summary
Esophageal cancer (EC) is one of the most aggressive cancer worldwide and contributes the sixth highest cancer-related mortality rate[1]. Disease carcinogenesis and prevention substantially distinctive between esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), with obvious differences in histological types[2]. ESCC accounts for up to 90% of esophageal cancer in the Asian population, which is characterized by ESCC treatments approaches such as surgery, chemotherapy, and radiotherapy, the overall 5-year survival rate is still unsatisfied[4]. Accumulating studies have reported lncRNAs are aberrantly expressed in human cancers and participate critically roles in diverse biological processes[6,7]. LncRNAs function as important regulators in gene expression networks in multiple ways, such as chromatin modification, transcription, and posttranscriptional regulation, which mainly depend on their subcellular localization[8]. HNF1A-AS1 in Official journal of the Cell Death Differentiation Association
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