Anchorage independency promoted tumor malignancy of melanoma cells under reattachment through elevated interleukin-8 and CXC chemokine receptor 1 expression

Abstract

Metastasis of melanoma cells during the recurrence or the late stage of melanoma has been characterized as the dissemination of tumor cells under anchorage independency. The secreted interleukin-8 (IL-8) and its conical receptors from melanoma cells have been associated with melanoma malignancy. However, their correlations with melanoma cells under anchorage independency were unclear. Suspension of adherent melanoma cells generated the suspended melanoma cell model of anoikis resistance. The in-vivo xenograft experiment, in-vitro cell proliferation/migration assay, microarray, and bioinformatics analysis were used to compare the malignancy and gene expression profiling in adherent and suspended melanoma cells. PCR, enzyme-linked immunosorbent assay, immunohistochemistry, and kinase inhibition assay were adapted to validate the expression and regulation of IL-8 and CXCR1/2. Suspended melanoma cells were anoikis resistant and showed elevated malignancy in vivo and in vitro. Gene expression profiling of adherent and suspended melanoma cells showed extensive alteration associated with cell survival/death, cell signaling, and regulation of gene expression. Microarray and bioinformatics analysis on gene set enrichment analysis further showed elevated IL-8 expression in suspended melanoma cells. The upregulation of IL-8 and the effect on chemotaxis were mediated by MEK/ERK activation upon cell suspension. Change in JNK phosphorylation induced CXCR1 downregulation under cell suspension, but upregulation by cell reattachment. We suggest the possible roles of elevated IL-8 secretion and change in CXCR expression contributing toward elevated melanoma malignancy upon reattachment from cell suspension. We show that the suspension of melanoma cells is critical in promoting melanoma malignancy in vivo and in vitro.

Accumulation of Circulating CCR7+ Natural Killer Cells Marks Melanoma Evolution and Reveals a CCL19-Dependent Metastatic Pathway

“…Indeed, both IL8 and CCL2 act as a tumor autocrine growth factors increasing melanoma cell migration in metastatic lesions (39,40). Thus, it is conceivable to speculate that these NK cell subsets may be able to migrate to the early melanoma metastatic foci.…”

Expression characteristic of CXCR1 in different breast tissues and the relevance between its expression and efficacy of neo-adjuvant chemotherapy in breast cancer

“…Furthermore, they could also have a direct effect in enhancing motor abilities and chemotaxis in tumor cells, as well as having indirect effect in promoting angiogenesis and the digestion of the extracellular matrix to promote tumor growth and metastasis by stimulating tumor growth [ 10 ]. It has been reported [ 11 – 14 ] that the use of CXCR1/CXCR2-specific antibodies in vitro can inhibit melanoma tumor growth.…”

25‐OH Vitamin D and Interleukin‐8: Emerging Biomarkers in Cutaneous Melanoma Development and Progression

“…In recent research studies, IL-8, an intense studied proangiogenic factor, was reported as one of the cytokines secreted by melanoma cells, influencing thus the differentiation pattern of keratinocytes and being a factor that mediates intercellular interactions in melanoma [ 32 ]. Moreover, it was shown that elevated IL-8 secretion and change in CXCR expression enhance melanoma malignancy [ 33 ]. Results performed in several solid cancers showed that serum IL-8 indicates tumor burden and prognosis in melanoma as well [ 34 ].…”