Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation
Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation
复制标题
DOI：
10.1038/ng.3568
复制
发表时间：
2016-07-01
期刊：
影响因子：
30.8
通讯作者：
Lin, Dongxin
中科院分区：
文献类型：
--
作者：
Zheng, Jian;Huang, Xudong;Lin, Dongxin
全基因组关联研究已经确定了与胰腺癌风险相关的几个位点;然而，遗传因素影响散发性胰腺癌发展的机制在很大程度上仍然未知。在这里，通过使用全基因组关联分析和功能表征，我们确定了一个长的基因间非编码RNA（lincRNA），LINC00673，作为一个潜在的肿瘤抑制基因，其种系变异与胰腺癌的风险。LINC00673能够增强PTPN11与PRPF19（一种E3泛素连接酶）的相互作用，并通过泛素化促进PTPN11降解，这导致SRC-ERK致癌信号传导减少和STAT1依赖性抗肿瘤反应的激活增强。LINC00673的外显子4中rs11655237处的G> A变化产生了miR-1231结合的靶位点，其以等位基因特异性方式减少LINC00673的作用，从而赋予对肿瘤发生的易感性。这些发现揭示了LINC00673在维持细胞稳态中的重要作用，以及其种系变异如何赋予胰腺癌易感性。
Genome-wide association studies have identified several loci associated with pancreatic cancer risk; however, the mechanisms by which genetic factors influence the development of sporadic pancreatic cancer remain largely unknown. Here, by using genome-wide association analysis and functional characterization, we identify a long intergenic noncoding RNA (lincRNA), LINC00673, as a potential tumor suppressor whose germline variation is associated with pancreatic cancer risk. LINC00673 is able to reinforce the interaction of PTPN11 with PRPF19, an E3 ubiquitin ligase, and promote PTPN11 degradation through ubiquitination, which causes diminished SRC-ERK oncogenic signaling and enhanced activation of the STAT1-dependent antitumor response. A G>A change at rs11655237 in exon 4 of LINC00673 creates a target site for miR-1231 binding, which diminishes the effect of LINC00673 in an allele-specific manner and thus confers susceptibility to tumorigenesis. These findings shed new light on the important role of LINC00673 in maintaining cell homeostasis and how its germline variation might confer susceptibility to pancreatic cancer.