The macrophage migration inhibitory factor (MIF) is a hypoxia regulated gene that has a variety of tumorigenic functions. In clear cell renal carcinoma (CCRC), hypoxic signaling is constitutively active because of the frequent loss of function of the von Hippel-Lindau tumor suppressor protein. We therefore sought to assess the expression of MIF in CCRC and its biological functions. We stained tumor tissue microarrays comprising sections of 128 CCRC tumors and found MIF to be moderately or highly expressed in >98%. MIF expression was further found to be dramatically elevated in blood plasma of individuals with CCRC compared with healthy controls, suggesting that measurement of MIF levels in the blood may have utility as a diagnostic marker in CCRC. At a functional level, MIF has been reported to engage the CD74 and CD44 receptors and induce signal transduction. In CCRC cell lines, depletion of MIF, CD74 or CD44 by small hairpin RNA led to a significant reduction in growth rate, and clonogenic survival, coinciding with the degree of knockdown. Interruption of the MIF pathway also decreased tumorigenic potential. Biochemically, we found that in CCRC cells MIF signaling leads to activation of the mitogen-activated protein kinase pathway and to Src phosphorylation, which is critical for regulation of p27. Together, our studies establish MIF as a protumorigenic signaling molecule that functions in an autocrine fashion to promote renal cell carcinoma and may be useful as a minimally invasive marker of disease status.
promoted these effects through the membrane receptor GPER1 located in lipid rafts and that inhibition of lipid rafts and GPER1 suppressed SLE serum-induced skin inflammation and expression of inflammatory molecules. Conclusions We conclude that oestrogen promotes the development of skin injury induced by SLE serum through the membrane receptor GPER1 and that lipid rafts play an important role in the regulatory effect of GPER1 in SLE skin inflammation. Background and aims Skin injury is the second most common clinical manifestation in patients with systemic lupus erythematosus (SLE), but its pathogenesis has not been thoroughly elucidated. Methods Based on skin deposition of IgG in SLE, we studied the features and mechanisms of intradermal IgG-induced skin inflammation Results We found that skin inflammation appeared at 3 hour and peaked at 3 d after intradermal injection of lupus IgG. This phenomenon was related to the dose of injected IgG but not to systemic disease activity. The severity of skin inflammation induced by lupus IgG was significantly decreased in mice depleted of monocytes and in mice deficient in TNF-a but not in mice lacking mature lymphocytes. Furthermore, lupus IgG promoted the progression of monocyte differentiation to dendritic cells (DCs) and enhanced the expression of TNF-a. TNF-a was found to stimulate the IgG-induced maturation of DCs and played a major role in the proliferation and activation of keratinocytes. Conclusions The results also indicate that the deposition of IgG in skin exerts an important role in the pathogenesis of skin injury in patients with SLE; therefore, blocking the IgG/ FcR signalling pathway can be a therapeutic target in skin lesions of patients with SLE. 211
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