Role of CXCL1 in tumorigenesis of melanoma

Abstract

The CXC chemokine, CXCL1 (melanoma growth-stimulatory activity/growth-regulated protein alpha), plays a major role in inflammation, angiogenesis, tumorigenesis, and wound healing. Recently, chemokines have been extensively related to cellular transformation, tumor growth, homing, and metastasis. CXCL1 and its mouse homologue MIP-2 have been shown to be involved in the process of tumor formation. When chemokines such as CXCL1 and CXCL8 (IL-8) become disregulated so that they are chronically expressed, tissue damage, angiogenesis, and tumorigenesis can follow. This up-regulation of chemokines has been attributed to constitutive activation of NF-kappaB. The constitutive NF-kappaB activation is an emerging hallmark in various types of tumors including breast, colon, pancreatic, ovarian, as well as melanoma. Previous findings from our laboratory and other laboratories have demonstrated the role of endogenous activation of NF-kappaB in association with enhanced metastatic potential of malignant melanoma cells and suggest that targeting NF-kappaB may have potential therapeutic effects in clinical trials. An important step in this direction would be to delineate the important intracellular pathways and upstream kinases involved in up-regulation of NF-kappaB in melanoma cells. In this review, the signaling pathways involved in the disregulation of NF-kappaB and chemokine expression are discussed.

Fig. 1

The pleiotropic role that chemokines play in promoting cellular transformation, tumor growth, invasion and homing, and metastasis to distant preferential organs. CXC and CC chemokines play multifunctional roles in facilitating tumor cell growth and invasion by augmenting their local angiogenic environment and up-regulating the expression of local proteinases to aid tumor cell invasion and entry into the circulation. Display of chemokine receptors on tumor cells may facilitate homing and organs that produce the chemokine ligands for those receptors. (Photocopied with permission from [23].)

Fig. 2

Transcription of CXCL1 is regulated through several cis elements including NF-κB, HMGI (Y), Sp1, and IUR. The IUR contains a binding site for the negative regulator, CDP, and PARP, an activator of transcription. In normal cells, CXCL1 is not induced, but it can be induced by IL-1β, LPS, and TNF-α during inflammation. During IL-1 induction and tumorigenesis, there is an increase in the nuclear levels of p65 and p50 subunits of NF-κB. In melanoma cells, NF-κB is activated constitutively. PARP displaces CDP, and CBP is proposed to bind NF-κB and Sp1 to stabilize the enhanceosome and keep the chromatin in an acetylated and active state.

Fig. 3

Model of potential components/upstream kinases involved in constitutive activation of NF-κB and thus chronic expression of CXCL1 in melanoma. The activation of these kinases can occur in an autocrine (by CXCL1) or paracrine (by cytokines and growth factors) manner. This constitutive expression can be blocked with the IKK inhibitor, NEMO-binding peptide, or PS341, a proteasome inhibitor and target tumor cells for apoptosis.

Fig. 4

Histological analysis of melanoma lesions that developed in association with overexpression of MIP-2 and loss of p16. (A) Typical cutaneous-pigmented melanoma lesion arising pigmented melanoma lesion arising in MIP-2-transgenic mice heterozygous for INK4a/ARF. (B) Morphology of the melanoma. (C) H&E staining of tissue section from a typical pigmented melanoma arising in MIP-2 transgenic mice. Melanoma formation in nude mice transplanted with MIP-2-transgenic melanocytes that were null for INK4a/ARF. Two million epidermal melanocytes derived from MIP-2-transgenic, newborn mouse completely deficient for INK4a/ARF were injected in the subscapular region of nude mice. (D) After 101 days of latency, skin melanoma lesions were observed. (E) H&E staining reveals the histological characteristics of a melanocytic tumor lesion. S-100 immunostaining of tumor cells in lung. (Photocopied with permission from ref. [117].)