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Published on: August 23, 2019
Linc-ROR inhibits NK cell-killing activity by promoting RXRA ubiquitination and reducing MICB expression in gastric
Qingbin Niu1,2, Zongrui Li2, He Jiang2
1Department of Gastrointestinal Surgery, Dongying People's Hospital, Dongying, China.
Abstract:
Linc-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.
Insights
Long noncoding RNA Linc-ROR promotes gastric cancer progression and immune evasion by degrading the RXRA protein, reducing MICB expression and NK cell activity. Linc-ROR is a potential therapeutic target for gastric cancer.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Gastric cancer (GC) remains a significant health concern with complex progression mechanisms.
- Long noncoding RNAs (lncRNAs) are increasingly recognized for their roles in cancer development.
- Linc-ROR has been implicated in various cancers, but its specific function in GC immune evasion requires elucidation.
Purpose of the Study:
- To investigate the role of Linc-ROR in gastric cancer progression and immune evasion.
- To identify the molecular mechanisms by which Linc-ROR influences anti-tumor immunity.
- To explore Linc-ROR as a potential therapeutic target for gastric cancer.
Main Methods:
- Reverse transcription polymerase chain reaction (RT-PCR) to quantify Linc-ROR expression.
- Co-culture experiments involving GC cells and Natural Killer (NK) cells (NK-92).
- Bioinformatics analysis to identify transcription factors regulating MICB expression.
- Ubiquitination and co-transfection assays to study protein-protein interactions and degradation pathways.
Main Results:
- Linc-ROR expression is upregulated in GC tissues and correlates with impaired NK cell-mediated immunity.
- Linc-ROR overexpression leads to decreased MICB expression on the cell surface by promoting RXRA degradation.
- Linc-ROR facilitates the ubiquitination and degradation of RXRA via interaction with UBE4B.
- This mechanism results in reduced NK cell-mediated killing of GC cells.
Conclusions:
- Linc-ROR acts as a tumor promoter in gastric cancer by enhancing immune evasion.
- The Linc-ROR/RXRA/MICB axis is crucial for regulating NK cell activity against GC.
- Targeting Linc-ROR may represent a novel therapeutic strategy for gastric cancer treatment.
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