期刊
CELL DEATH & DISEASE
卷 12, 期 6, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41419-021-03858-7
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资金
- National Nature Science Foundation of China [81871894, 91942314]
- State Key Laboratory of Esophageal Cancer Prevention and Treatment of China [K2020-004]
The study reveals that upregulated lncRNA DGCR5 promotes proliferation, migration, and invasion of ESCC cells while inhibiting apoptosis. DGCR5 directly binds to SRSF1, increasing its stability and initiating important isoform switch of Mcl-1. Cell-derived xenograft model confirms DGCR5's role in facilitating ESCC tumorigenesis.
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.
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