Macrophage migration inhibitory factor engages PI3K/Akt signalling and is a prognostic factor in metastatic melanoma

Abstract

BackgroundMacrophage migration inhibitory factor (MIF) is a widely expressed cytokine involved in a variety of cellular processes including cell cycle regulation and the control of proliferation. Overexpression of MIF has been reported in a number of cancer types and it has previously been shown that MIF is upregulated in melanocytic tumours with the highest expression levels occurring in malignant melanoma. However, the clinical significance of high MIF expression in melanoma has not been reported.MethodsMIF expression was depleted in human melanoma cell lines using siRNA-mediated gene knockdown and effects monitored using in vitro assays of proliferation, cell cycle, apoptosis, clonogenicity and Akt signalling. In silico analyses of expression microarray data were used to correlate MIF expression levels in melanoma tumours with overall patient survival using a univariate Cox regression model.ResultsKnockdown of MIF significantly decreased proliferation, increased apoptosis and decreased anchorage-independent growth. Effects were associated with reduced numbers of cells entering S phase concomitant with decreased cyclin D1 and CDK4 expression, increased p27 expression and decreased Akt phosphorylation. Analysis of clinical outcome data showed that MIF expression levels in primary melanoma were not associated with outcome (HR = 1.091, p = 0.892) whereas higher levels of MIF in metastatic lesions were significantly associated with faster disease progression (HR = 2.946, p = 0.003 and HR = 4.600, p = 0.004, respectively in two independent studies).ConclusionsOur in vitro analyses show that MIF functions upstream of the PI3K/Akt pathway in human melanoma cell lines. Moreover, depletion of MIF inhibited melanoma proliferation, viability and clonogenic capacity. Clinically, high MIF levels in metastatic melanoma were found to be associated with faster disease recurrence. These findings support the clinical significance of MIF signalling in melanoma and provide a strong rationale for both targeting and monitoring MIF expression in clinical melanoma.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-630) contains supplementary material, which is available to authorized users.

Involvement of macrophage migration inhibitory factor in cancer and novel therapeutic targets

“…One previous study demonstrated that MIF expression was downregulated by short hairpin (sh)RNA in the murine ovarian cancer ID8 cell line, and the proliferation of inoculated tumor cells was reduced when compared with mock-transfected cells, as revealed by a decrease in the percentage of Ki-67-immunopositive cells (39). MIF-silencing studies have revealed comparable reductions in the tumor cell proliferation of human melanoma and hepatocellular carcinoma cell lines, whereby a decrease in cyclin D1 expression was reported in vitro and in vivo, respectively (31,20). Another study reported that cyclin-dependent kinase 4, cyclin D2 and cyclin E2 expression was downregulated following MIF-knockdown in HeLa 229 cells (22).…”

“…In oral squamous cell carcinoma, increased MIF expression correlates with a higher pathological (p)T and pN status, positive perineural invasion and tumor depth (30). In addition, in metastatic melanoma, high MIF expression is associated with faster disease progression (31). In addition, high MIF mRNA expression in pancreatic ductal carcinoma correlates with a poor survival when compared with tumors exhibiting low MIF mRNA expression (32).…”

“…(35) demonstrated that MIF interacts with the CD74/CD44 receptor complex in stably transfected mammalian kidney COS-7/M6 cells, leading to MIF signal transduction via the activation of Src, Ras, MAPK kinase and extracellular-signal-regulated kinase (ERK). It is hypothesized that this pathway may account for enhanced proliferative activity (31). Indeed, the interaction of MIF with its receptor CD74 results in the stimulation of ERK1/2 leading to cyclin D1 expression (36) and enhancement of proliferative activity (35).…”

miR-194 Suppresses Proliferation and Migration and Promotes Apoptosis of Osteosarcoma Cells by Targeting CDH2

“…Aberrant expression of miRNAs has been observed in human cancers and has been shown to be involved in a variety of critical cellular processes, including cell differentiation, proliferation and metabolism [4]. The alterations in miRNA expression may play a crucial role in the initiation and progression of cancers [5], functioning as a novel class of oncogenes or tumour suppressors [6, 7]. Previous studies showed that miR-194 has functioned as a tumour suppressor in various types of cancers [8-10].…”

Análise do fator inibitório da migração de macrófagos (MIF) associado a via de sinalização PI3K/AKT na carcinogênese oral

“…Em várias lesões potencialmente malignas e malignas tem sido relatado aumento da expressão de MIF correlacionando com a evolução e mau prognóstico da doença (6). Esta proteína atua não somente a migração e invasão celular (46), mas também na proliferação, evasão de apoptose e invasão (25), mostrando que a sua baixa expressão reduz a invasão tumoral (53).…”