Genome-wide association studies (GWAS) have identified multiple gastric cancer risk loci and several protein-coding susceptibility genes. However, the role of long-noncoding RNAs (lncRNAs) transcribed from these risk loci in gastric cancer development and progression remains to be explored. Here, we functionally characterize a lncRNA, lncPSCA, as a novel tumor suppressor whose expression is fine-regulated by a gastric cancer risk-associated genetic variant. The rs2978980 T > G change in an intronic enhancer of lncPSCA interrupts binding of transcription factor RORA, which down-regulates lncPSCA expression in an allele-specific manner. LncPSCA interacts with DDX5 and promotes DDX5 degradation through ubiquitination. Increased expression of lncPSCA results in low levels of DDX5, less RNA polymerase II (Pol II) binding with DDX5 in the nucleus, thus activating transcription of multiple p53 signaling genes by Pol II. These findings highlight the importance of functionally annotating lncRNAs in GWAS risk loci and the great potential of modulating lncRNAs as innovative cancer therapy.

中文翻译：

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8q24.3 风险基因座中的 LncPSCA 通过破坏 DDX5 驱动胃癌

全基因组关联研究（GWAS）已经确定了多个胃癌风险位点和几个蛋白质编码易感基因。然而，从这些风险位点转录的长链非编码 RNA (lncRNA) 在胃癌发展和进展中的作用仍有待探索。在这里，我们在功能上将 lncRNA lncPSCA 描述为一种新型肿瘤抑制因子，其表达受到胃癌风险相关遗传变异的精细调节。lncPSCA 内含子增强子的rs2978980 T > G 变化中断转录因子 RORA 的结合，从而以等位基因特异性方式下调 lncPSCA 表达。LncPSCA 与 DDX5 相互作用并通过泛素化促进 DDX5 降解。lncPSCA 表达增加导致 DDX5 水平降低，核内与 DDX5 结合的 RNA 聚合酶 II (Pol II) 减少，从而激活 Pol II 对多个 p53 信号基因的转录。这些发现强调了在 GWAS 风险位点功能注释 lncRNA 的重要性以及调节 lncRNA 作为创新癌症治疗的巨大潜力。