Abstract
Long non-coding RNAs (LncRNAs) play important roles in the development of human esophageal squamous cell carcinoma (ESCC). Our previous studies have shown that knockdown of LncRNA ESCCAL-1 expression inhibits the growth of ESCC cells, but the mechanisms remain largely unknown. In this study, we show that over-expression of ESCCAL-1 promotes ESCC cell proliferation and cell-cycle progression by blocking ubiquitin-mediated degradation of an oncoprotein galectin-1 (Gal-1). Multiple LncRNA expression datasets as well as our own data together reveal that ESCCAL-1 is evidently up-regulated in ESCC tissues and exhibits promising diagnostic value. Over-expression of ESCCAL-1 augmented ESCC cell proliferation and cell-cycle progression, whereas down-regulation of ESCCAL-1 resulted in the opposite effects. Mechanistically, LncRNA ESCCAL-1 directly binds to Gal-1 and positively regulates its protein level without affecting its mRNA level. Up-regulation of Gal-1 facilitated ESCC cell proliferation and cell-cycle progress. Knockdown of Gal-1 mitigated the effects of ESCCAL-1-mediated high cellular proliferation, NF-κB signaling activation and tumorigenicity of ESCC cells. Thus, our findings provide novel insight into the mechanism by which ESCCAL-1 facilitates ESCC tumorigenesis and cell-cycle progression by interacting with and stabilizing Gal-1 protein, suggesting a potential therapeutic target for ESCC.
Highlights
Esophageal cancer (ESCA) is one of the most frequently diagnosed malignancies globally and is the sixth leading cause of cancerinduced death worldwide[1,2]
Multiple transcriptional datasets reveal ESCCAL-1 overexpression as a potential diagnostic biomarker for esophageal squamous cell carcinoma (ESCC) By analyzing the Long non-coding RNAs (LncRNAs) expression data of GSE120356 (5 pairs of ESCC specimens) and GSE53622 (60 pairs of ESCC specimens) from GEO, we found that ESCCAL-1 was one of the most significantly upregulated lncRNAs in ESCC compared to the matched normal tissues (Fig. 1A)
The expression of ESCCAL-1 was upregulated in 5 ESCC cell lines (Fig. 1G), which was consistent with its expression in tissues
Summary
Esophageal cancer (ESCA) is one of the most frequently diagnosed malignancies globally and is the sixth leading cause of cancerinduced death worldwide[1,2]. Despite significant advances in cancer diagnosis and treatment in recent decades, there is a lack of effective clinical treatment strategies for ESCA. According to the Global Cancer Statistics Report 20122 and 20206, the number of new cases of ESCA increased from 323,000 to 604,100, and deaths from 281,200 to 544,076 each year. The five-year overall survival (OS) rate for ESCA patients is only about 20%, even in developed countries[1,7,8]. This is mainly due to tumor recurrence and uncontrolled growth driven by key molecules[9,10]. Identifying the key molecules that regulate ESCA progression and revealing the mechanisms of action may provide novel insights for the development of effective diagnostic markers and therapeutic targets.
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