Linc‐ROR inhibits NK cell‐killing activity by promoting RXRA ubiquitination and reducing MICB expression in gastric cancer patients

Abstract

AbstractLinc‐ROR plays an important role in gastric cancer (GC) development and progression. This study sought to determine how the aberrant expression of Linc‐ROR impacts GC progression and immune evasion, and to identify new targets for GC therapy. GC cells overexpressing Linc‐ROR and GSAGS cells were cocultured with NK‐92 cells, respectively, and Linc‐ROR expression was determined using reverse transcription polymerase chain reaction. Linc‐ROR overexpression experiments were used to measure the expression of MICB, a tumor protein that is recognized by natural killer (NK) cells. Bioinformatics analysis identified retinoid X receptor α (RXRA) and YY1 as MICB‐specific transcription factors. Cotransfection and ubiquitinated drug experiments found that Linc‐ROR promoted the ubiquitination and degradation of RXRA. Linc‐ROR was upregulated in GC tissue and high expression was associated with tumor escape from NK‐92 cell‐mediated immunity. Linc‐ROR overexpression inhibited the expression of MICB on the cell surface by degrading RXRA. These findings indicate that Linc‐ROR promotes the binding of RXRA and E3 ligase UBE4B, reducing RXRA and MICB expression, and limiting NK cell‐killing activity. Linc‐ROR is a critical long noncoding RNA with a tumor‐promoting function in GC and thus may serve as a potential therapeutic target.