AXL Transcriptionally Up-regulates ISG15 Expression to Mediate Cell Proliferation in Non-small-cell Lung Cancer Cells

Background/Aim: The AXL receptor tyrosine kinase (AXL) has been identified as a key driver of tumor progression and chemoresistance in non-small-cell lung cancer (NSCLC). However, the molecular mechanisms underlying AXL-mediated oncogenesis remain unclear. This study aimed to identify novel AXL downstream genes involved in NSCLC progression.

Materials and Methods: Transcriptomic RNA sequencing and analysis were performed to identify genes downstream from AXL. Cellular proliferation was assessed using the CCK-8 assay. Glucose uptake was measured using a glucose uptake assay. mRNA expression levels of interferon-stimulated gene 15 (ISG15) were analyzed via reverse transcription–quantitative polymerase chain reaction, and the regulation of ISG15 transcription by AXL was evaluated through an ISG15 promoter activity assay.

Results: Transcriptomic RNA sequencing revealed ISG15 as a novel downstream target of AXL. ISG15 expression significantly enhanced cellular proliferation and glucose uptake in NSCLC cells. AXL transcriptionally upregulated ISG15 expression by modulating its 5′-promoter activity.

Conclusion: ISG15 is a newly identified target of AXL and may serve as a potential therapeutic target to overcome resistance in patients with NSCLC receiving AXL-targeted therapies.