IL-8 regulates the stemness properties of cancer stem cells in the small-cell lung cancer cell line H446

Abstract

PurposeCancer 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 methodsWhole 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.ResultsIn 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.ConclusionIL-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.

Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy

“…Overexpresson of CXCL8 promotes cell proliferation and migration through EMT, PI3K-Akt signaling, and E-cadherin downregulation in triple-negative breast cancer [ 127 ]. CXCL8 enhances the stemness properties of the self-renewal capability, expression of stemness-related genes, and tumorigenicity in small-cell lung cancer sphere-forming cells [ 128 ]. IL-6 and CXCL8 promote EMT and cell invasion through STAT3 signaling in oral cancer [ 129 ].…”

Regulation of Tumor and Metastasis Initiation by Chemokine Receptors

“…As expected, the IL-8-CXCR1/2 axis also regulates the expression of pluripotency-associated genes. In small-cell lung cancer, IL-8 transcript expression and protein secretion is increased in MICs, and this chemokine acts in an autocrine fashion to induce stemness features including self-renewal, migration, tumorsphere formation, and the expression of stemness related genes 100 . Knock-down of IL-8 in these MICs led to a decrease in OCT4 and NANOG expression as well as an inhibition of tumor growth in a mouse xenograft model, while treatment with exogenous recombinant human IL-8 upregulated SOX2 and NANOG in vitro 100 .…”

“…In small-cell lung cancer, IL-8 transcript expression and protein secretion is increased in MICs, and this chemokine acts in an autocrine fashion to induce stemness features including self-renewal, migration, tumorsphere formation, and the expression of stemness related genes 100 . Knock-down of IL-8 in these MICs led to a decrease in OCT4 and NANOG expression as well as an inhibition of tumor growth in a mouse xenograft model, while treatment with exogenous recombinant human IL-8 upregulated SOX2 and NANOG in vitro 100 . CXCR1/2 and their ligands are both expressed by lung cancer cells, and receptor inhibition with an antagonist decreased migration and enhanced apoptosis in vitro and suppressed tumor growth, metastasis, and angiogenesis in a mouse xenograft model 101 .…”

Interleukin-8 in Melanoma Pathogenesis, Prognosis and Therapy—An Integrated View into Other Neoplasms and Chemokine Networks

“…IL-8 binding to IL-8Rs induces conformational changes in receptor intracellular loops and C-tail and couple them to heteromeric small G-proteins (Gαβγ). The multiple cell types which express IL-8 and IL-8Rs presented in Table 1 [ 23 , 28 , 30 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ]. This diversity demonstrates how the fate of other tissues may interfere with the evolution of the neoplastic cells, including melanoma, which express both IL-8 and IL-8Rs.…”