Gene Expression Changes in Cytokine and Chemokine Receptors in Association with Melanoma Liver Metastasis

Abstract

Cytokines and chemokines (chemotactic cytokines) are soluble extracellular proteins that bind to specific receptors and play an integral role in the cell-to-cell signaling network. In addition, they can promote the homing of cancer cells into different organs. We investigated the potential relationship between human hepatic sinusoidal endothelial cells (HHSECs) and several melanoma cell lines for the expression of chemokine and cytokine ligands and receptor expression during the invasion of melanoma cells. In order to identify differences in gene expression related to invasion, we selected invasive and non-invasive subpopulations of cells after co-culturing with HHSECs and identified the gene expression patterns of 88 chemokine/cytokine receptors in all cell lines. Cell lines with stable invasiveness and cell lines with increased invasiveness displayed distinct profiles of receptor genes. Cell lines with increased invasive capacity after culturing with conditioned medium showed a set of receptor genes (CXCR1, IL1RL1, IL1RN, IL3RA, IL8RA, IL11RA, IL15RA, IL17RC, and IL17RD) with significantly different expressions. It is very important to emphasize that we detected significantly higher IL11RA gene expression in primary melanoma tissues with liver metastasis as well, compared to those without metastasis. In addition, we assessed protein expression in endothelial cells before and after co-culturing them with melanoma cell lines by applying chemokine and cytokine proteome arrays. This analysis revealed 15 differentially expressed proteins (including CD31, VCAM-1, ANGPT2, CXCL8, and CCL20) in the hepatic endothelial cells after co-culture with melanoma cells. Our results clearly indicate the interaction between liver endothelial and melanoma cells. Furthermore, we assume that overexpression of the IL11RA gene may play a key role in organ-specific metastasis of primary melanoma cells to the liver.

Inhibiting IL11RA to mitigate hepatic metastasis in skin cutaneous melanoma: Comprehensive insights from in vitro and in vivo investigations

“… 12 However, a previous study emphasized the overexpression of the IL11RA gene in the organ‐specific metastasis of primary melanoma cells to the liver, indicating its involvement in the interaction between liver endothelial and melanoma cells. 13 Our study found elevated IL11RA expression in various human SKCM cell lines compared to normal cells. IL11RA downregulation significantly inhibited the migratory and invasive capabilities of SKCM cells.…”

“…A cytokine profile analysis revealed lower expression of IL‐11RA in tumor‐positive sentinel nodes compared to tumor‐negative sentinel nodes in melanoma 12 . However, a previous study emphasized the overexpression of the IL11RA gene in the organ‐specific metastasis of primary melanoma cells to the liver, indicating its involvement in the interaction between liver endothelial and melanoma cells 13 . Our study found elevated IL11RA expression in various human SKCM cell lines compared to normal cells.…”

“…12 Notably, IL11RA overexpression in melanoma is linked to organ-specific metastasis to the liver, as evidenced by its significantly higher expression in tissues with liver metastasis. 13 Despite these insights, the precise role of IL11RA in the progression of cutaneous melanoma, particularly its impact on liver metastasis, remains incompletely understood. This study aims to bridge this knowledge gap by investigating the specific contributions of IL11RA to melanoma metastasis, with a focus on its association with liver metastases.…”

“…In early melanoma, IL11RA exhibits varied expression, potentially influencing the cytokine profile associated with metastasis to regional lymph nodes 12 . Notably, IL11RA overexpression in melanoma is linked to organ‐specific metastasis to the liver, as evidenced by its significantly higher expression in tissues with liver metastasis 13 …”

“… 12 Notably, IL11RA overexpression in melanoma is linked to organ‐specific metastasis to the liver, as evidenced by its significantly higher expression in tissues with liver metastasis. 13 …”