Purpose: Cancer stem cells (CSCs) are a small population of cancer cells located within a tumor that are highly tumorigenic, capable of tumor initiation, and resistant to cancer therapies. We identified the potential genes involved in regulating stemness properties and investigated the mechanisms in small-cell lung cancer (SCLC).
Materials and methods: Whole transcriptome sequencing technology was used to screen the potential genes involved in regulating stemness properties from SCLC-SCs (uPAR⁺) and differentiated cells (uPAR^-) in the H446 cell line. The selected genes were validated by quantitative reverse transcription PCR and ELISAs. The effect of IL-8 on stemness of sphere-forming cells was determined through tumor sphere formation, wound healing migration, and in vivo tumorigenesis assays.
Results: In our study, uPAR⁺ and uPAR^- cells showed different gene expression profiles. IL-8 was upregulated in SCLC sphere-forming cells. Blocking IL-8 expression with siRNA led to loss of stemness, including the self-renewal capability, migration, expression of stemness-related genes, and in vivo tumorigenicity, in sphere-forming cells. Consistently, exogenously added IL-8 enhanced stemness properties in parental cells.
Conclusion: IL-8 was upregulated in SCLC sphere-forming cells, and critical for the acquisition and/or maintenance of the stemness features in the SCLC cell line H446. Our results suggest that blocking IL-8 signaling may provide a novel therapeutic approach for targeting SCLC-SCs and improve treatment and outcomes in SCLC.
Keywords: small-cell lung cancer, cancer stem cells, tumor sphere, IL-8, uPAR, stemness