Abstract
Recent evidence indicates that E2F1 transcription factor have pivotal roles in the regulation of cellular processes, and is found to be dysregulated in a variety of cancers. Long non-coding RNAs (lncRNAs) are also reported to exert important effect on tumorigenesis. E2F1 is aberrantly expressed in gastric cancer (GC), and biology functions of E2F1 in GC are controversial. The biological characteristics of E2F1 and correlation between E2F1 and lncRNAs in GC remain to be found. In this study, integrated analysis revealed that E2F1 expression was significantly increased in GC cases and its expression was positively correlated with the poor pathologic stage, large tumor size and poor prognosis. Forced E2F1 expression promotes proliferation, whereas loss of E2F1 function decreased cell proliferation by blocking of cell cycle in GC cells. Mechanistic analyses indicated that E2F1 accelerates GC growth partly through induces TINCR transcription. TINCR could bind to STAU1 (staufen1) protein, and influence CDKN2B mRNA stability and expression, thereby affecting the proliferation of GC cells. Together, our findings suggest that E2F1/TINCR/STAU1/CDKN2B signaling axis contributes to the oncogenic potential of GC and may constitute a potential therapeutic target in this disease.
Highlights
Gastric cancer (GC) is still one of the most significant health problems in the world with high frequencies in East Asia.[1]
Our results showed that E2F1 was predominantly located in the nucleus of GC cells (Figure 1c)
The results showed that the expression levels of E2F1 were significantly increased in all tumourigenic GC cell lines than that in non-tumourigenic cell lines (Figure 1e)
Summary
Gastric cancer (GC) is still one of the most significant health problems in the world with high frequencies in East Asia.[1]. TINCR, a long non-coding RNA (lncRNA) producing a 3.7-kb transcript, was first reported to bind to staufen[1] (STAU1) protein and mediate differentiated mRNA stabilization.[15] STAU1 protein is a double-stranded RNA-binding protein, and has various roles in gene expression. STAU1 binds to an STAU1-binding site in the 3′-untranslated region (3′-UTR) of its target mRNAs inducing mRNA degradation, which is termed STAU1-mediated mRNA decay (SMD).[16] SMD is a translation-dependent mechanism that occurs when STAU1, together with the nonsense-mediated mRNA decay factor UPF1, is bound sufficiently downstream of a termination codon.[16] Recently, we found that the expression of TINCR was elevated at the mRNA levels in GC cells and tissues and the upregulation of TINCR is induced by the transcription factor SP1.17 TINCR regulates cell growth, cell cycle progression by affecting KLF2 mRNA stability via SMD.[17]. We found that: (a) E2F1 could promote GC proliferation and cell cycle progression; (b) patients with high E2F1 expression in their GC cells have a poor prognosis; (c) E2F1 could induce TINCR transcription activation; and (d) TINCR forces cell growth, cell cycle progression by affecting CDKN2B mRNA stability via SMD
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