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


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Article Info

DATE

2014-08-29

AUTHORS

Camila S Oliveira, Charles E de Bock, Timothy J Molloy, Elham Sadeqzadeh, Xin Yan Geng, Peter Hersey, Xu Dong Zhang, Rick F Thorne

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. More... »

PAGES

630

References to SciGraph publications

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    http://scigraph.springernature.com/pub.10.1186/1471-2407-14-630

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    http://dx.doi.org/10.1186/1471-2407-14-630

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/25168062


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    36 schema:description 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.
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    42 schema:keywords Akt
    43 Akt pathway
    44 Akt phosphorylation
    45 BackgroundMacrophage migration inhibitory factor
    46 CDK4 expression
    47 ConclusionsOur
    48 Cox regression model
    49 D1
    50 MIF expression
    51 MIF expression levels
    52 MIF function
    53 MIF levels
    54 PI3K/Akt
    55 PI3K/Akt pathway
    56 analysis
    57 anchorage-independent growth
    58 apoptosis
    59 assays
    60 assays of proliferation
    61 cancer types
    62 capacity
    63 cell cycle
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    65 cell lines
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    69 clinical outcome data
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    74 control
    75 control of proliferation
    76 cycle
    77 cycle regulation
    78 cyclin D1
    79 cytokines
    80 data
    81 depletion
    82 disease progression
    83 disease recurrence
    84 effect
    85 expression
    86 expression levels
    87 expression microarray data
    88 factors
    89 faster disease progression
    90 findings
    91 function
    92 gene knockdown
    93 growth
    94 high MIF expression
    95 high expression levels
    96 high levels
    97 higher MIF levels
    98 human melanoma cell lines
    99 inhibitory factor
    100 knockdown
    101 lesions
    102 levels
    103 lines
    104 malignant melanoma
    105 melanocytic tumors
    106 melanoma
    107 melanoma cell lines
    108 melanoma proliferation
    109 melanoma tumors
    110 metastatic lesions
    111 metastatic melanoma
    112 microarray data
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    114 model
    115 number
    116 outcome data
    117 outcomes
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    119 overexpression
    120 p27 expression
    121 pathway
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    123 phase concomitant
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    125 primary melanoma
    126 process
    127 prognostic factors
    128 progression
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    130 rationale
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    132 reduced number
    133 regression models
    134 regulation
    135 siRNA-mediated gene knockdown
    136 significance
    137 silico analysis
    138 strong rationale
    139 survival
    140 tumors
    141 types
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    143 variety
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