RNA editing of <i>SLC22A3</i> drives early tumor invasion and metastasis in familial esophageal cancer

Abstract

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 <i>SLC22A3</i> 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 <i>SLC22A3</i> 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 <i>ADAR2</i>, a familial ESCC susceptibility gene identified by our post hoc genome-wide association study, is positively correlated with the editing level of <i>SLC22A3</i> Moreover, functional studies showed that <i>SLC22A3</i> is a metastasis suppressor in ESCC, and deregulation of <i>SLC22A3</i> 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 <i>SLC22A3</i> contributes to the early development and progression of familial esophageal cancer in high-risk individuals.