RNA editing of SLC22A3 drives early tumor invasion and metastasis in familial esophageal cancer

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 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 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 SLC22A3 contributes to the early development and progression of familial esophageal cancer in high-risk individuals.

Keywords: ADAR2; RNA editing; SLC22A3; familial ESCC; metastasis suppressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actinin / metabolism
  • Adenosine Deaminase / genetics
  • Adenosine Deaminase / metabolism
  • Adult
  • Aged
  • Animals
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / secondary
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement
  • Disease Progression
  • Down-Regulation
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / pathology
  • Esophageal Neoplasms / secondary
  • Esophageal Squamous Cell Carcinoma
  • Esophagus / cytology
  • Esophagus / metabolism
  • Gene Knockdown Techniques
  • Genome-Wide Association Study
  • Humans
  • Lymphatic Metastasis / genetics
  • Male
  • Mice
  • Mice, SCID
  • Middle Aged
  • Neoplasm Invasiveness / genetics
  • Organic Cation Transport Proteins / deficiency
  • Organic Cation Transport Proteins / genetics*
  • Organic Cation Transport Proteins / metabolism
  • RNA Editing*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Risk Factors


  • ACTN4 protein, human
  • Organic Cation Transport Proteins
  • RNA-Binding Proteins
  • solute carrier family 22 (organic cation transporter), member 3
  • Actinin
  • ADARB1 protein, human
  • Adenosine Deaminase