Department of Pharmacology, Shenzhen University School of Medicine, Shenzhen, China 518060;
Cancer Research Centre, Health Science Center, Shenzhen University, Shenzhen, China 518060.
Proc Natl Acad Sci U S A. 2017 Jun 6;114(23):E4631-E4640. doi: 10.1073/pnas.1703178114. Epub 2017 May 22.
Like many complex human diseases, esophageal squamous cell carcinoma (ESCC) is known to cluster in families. Familial ESCC cases often show early onset and worse prognosis than the sporadic cases. However, the molecular genetic basis underlying the development of familial ESCC is mostly unknown. We reported that is significantly down-regulated in nontumor esophageal tissues from patients with familial ESCC compared with tissues from patients with sporadic ESCCs. A-to-I RNA editing of the gene results in its reduced expression in the nontumor esophageal tissues of familial ESCCs and is significantly correlated with lymph node metastasis. The RNA-editing enzyme , a familial ESCC susceptibility gene identified by our post hoc genome-wide association study, is positively correlated with the editing level of Moreover, functional studies showed that is a metastasis suppressor in ESCC, and deregulation of facilitates cell invasion and filopodia formation by reducing its direct association with α-actinin-4 (ACTN4), leading to the increased actin-binding activity of ACTN4 in normal esophageal cells. Collectively, we now show that A-to-I RNA editing of contributes to the early development and progression of familial esophageal cancer in high-risk individuals.
与许多复杂的人类疾病一样，食管鳞状细胞癌 (ESCC) 已知在家族中聚集。家族性 ESCC 病例的发病年龄通常较早，预后比散发性病例差。然而，家族性 ESCC 发病的分子遗传基础在很大程度上尚不清楚。我们报道与散发性 ESCC 患者的非肿瘤食管组织相比，家族性 ESCC 患者的非肿瘤食管组织中 显著下调。 基因的 A-to-I RNA 编辑导致其在家族性 ESCC 的非肿瘤食管组织中表达减少，并且与淋巴结转移显著相关。RNA 编辑酶 ，是我们通过事后全基因组关联研究发现的家族性 ESCC 易感性基因，与 的编辑水平呈正相关。此外，功能研究表明 在 ESCC 中是一种转移抑制因子，通过降低其与 α-辅肌动蛋白-4 (ACTN4) 的直接关联， 失活促进细胞侵袭和片状伪足形成，导致正常食管细胞中 ACTN4 的肌动蛋白结合活性增加。总之，我们现在表明， 的 A-to-I RNA 编辑导致高危个体中家族性食管癌的早期发生和进展。
