RNA editing of SLC22A3 drives early tumor invasion and metastasis in familial esophageal cancer
RNA editing of SLC22A3 drives early tumor invasion and metastasis in familial esophageal cancer
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DOI：
10.1073/pnas.1703178114
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发表时间：
2017-06-06
影响因子：
11.1
通讯作者：
Guan, Xin-Yuan
中科院分区：
文献类型：
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作者：
Fu, Li;Qin, Yan-Ru;Guan, Xin-Yuan
像许多复杂的人类疾病一样，食管鳞状细胞癌（ESCC）已知在家庭中聚集。家族性食管鳞癌发病早，预后差。然而，家族性ESCC发展的分子遗传基础大多未知。我们报道，与散发性食管鳞癌患者的组织相比，家族性食管鳞癌患者的非肿瘤食管组织中SLC 22 A3表达显著下调。SLC 22 A3基因的A-to-IRNA编辑导致其在家族性ESCC的非肿瘤食管组织中的表达降低，并且与淋巴结转移显著相关。RNA编辑酶ADAR 2是一个家族性ESCC易感基因，通过我们的事后全基因组关联研究确定，与SLC 22 A3的编辑水平呈正相关。此外，功能研究表明，SLC 22 A3是ESCC中的转移抑制因子，并且SLC 22 A3的失调通过减少其与α-辅肌动蛋白-4（ACTN 4）的直接缔合而促进细胞侵袭和丝状伪足形成，导致正常食管细胞中ACTN 4的肌动蛋白结合活性增加。总的来说，我们现在表明SLC 22 A3的A到I RNA编辑有助于高危个体家族性食管癌的早期发展和进展。
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 SLC22A3 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 SLC22A3 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 ADAR2, a familial ESCC susceptibility gene identified by our post hoc genome-wide association study, is positively correlated with the editing level of SLC22A3. Moreover, functional studies showed that SLC22A3 is a metastasis suppressor in ESCC, and deregulation of SLC22A3 facilitates cell invasion and filopodia formation by reducing its direct association with alpha-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 SLC22A3 contributes to the early development and progression of familial esophageal cancer in high-risk individuals.