Macrophage migration inhibitory factor regulates mitochondrial dynamics and cell growth of human cancer cell lines through CD74–NF-κB signaling

Abstract

The indispensable role of macrophage migration inhibitory factor (MIF) in cancer cell proliferation is unambiguous, although which specific roles the cytokine plays to block apoptosis by preserving cell growth is still obscure. Using different cancer cell lines (AGS, HepG2, HCT116, and HeLa), here we report that the silencing of MIF severely deregulated mitochondrial structural dynamics by shifting the balance toward excess fission, besides inducing apoptosis with increasing sub-G 0 cells. Furthermore, enhanced mitochondrial Bax translocation along with cytochrome c release, down-regulation of Bcl-xL, and Bcl-2 as well as up-regulation of Bad, Bax, and p53 indicated the activation of a mitochondrial pathway of apoptosis upon MIF silencing. The data also indicate a concerted down-regulation of Opa1 and Mfn1 along with a significant elevation of Drp1, cumulatively causing mitochondrial fragmentation upon MIF silencing. Upregulation of Drp1 was found to be further coupled with fissogenic serine 616 phosphorylation and serine 637 dephosphorylation, thus ensuring enhanced mitochondrial translocation. Interestingly, MIF silencing was found to be associated with decreased NF-B activation. In fact, NF-B knockdown in turn increased mitochondrial fission and cell death. In addition, the silencing of CD74, the cognate receptor of MIF, remarkably increased mitochondrial fragmentation in addition to preventing cell proliferation, inducing mitochondrial depolarization, and increasing apoptotic cell death. This indicates the active operation of a MIF-regulated CD74 -NF-B signaling axis for maintaining mitochondrial stability and cell growth. Thus, we propose that MIF, through CD74, constitutively activates NF-B to control mitochondrial dynamics and stability for promoting carcinogenesis via averting apoptosis.

Macrophage migration inhibitory factor facilitates the therapeutic efficacy of mesenchymal stem cells derived exosomes in acute myocardial infarction through upregulating miR-133a-3p

“…MIF is a pro-inflammatory cytokine that is widely expressed in many kinds of cells including MSCs [ 11 ]. Recent studies have shown that MIF plays an important role in cell survival and proliferation, and our previous study demonstrated that exosomes from MSCs with overexpression of MIF had better cardiac protection in rats with AMI [ 12 , 13 ]. In the present study, umbilical cord MSCs (ucMSCs) were infected with lentivirus containing MIF (MIF-MSC).…”

Single‐cell transcriptome analysis revealed the heterogeneity and microenvironment of gastrointestinal stromal tumors

“…As expected, collagen proteins tightly connected GISTs and adipose endothelial cells spatially (Figure 5B). CD74 were found to be highly involved in such interactions by binding secreted proteins and cell surface receptors, such as MIF, APP, and COPA (Figure 5B), thus are likely to playing an important role in promoting tumor progression, according to previous research 45‐48 …”

“…CD74 were found to be highly involved in such interactions by binding secreted proteins and cell surface receptors, such as MIF, APP, and COPA ( Figure 5B), thus are likely to playing an important role in promoting tumor progression, according to previous research. [45][46][47][48] Additionally, we found some interactions uniquely from adipose endothelial cells ( Figure 5B, in the red boxes) that might affect tumor growth. First, adipose endothelial cells expressed LAGLS9…”

MIF Facilitates the Therapeutic Efficacy of Mesenchymal Stem Cells Derived Exosomes in Acute Myocardial Infarction Through Up-regulating miR-133a-3p

“…Our previous study showed that exosomes from MSCs with overexpression of MIF compared with MSCs had better cardiac protection in rats with AMI. 12,13 In this study, we explored the mechanism of exosomes from MIF engineered umbilical cord MSCs (ucMSCs) in cardiac protective function. In vitro, we found that exosomes from MIF engineered ucMSCs (MIF-Exo) had the better effects of cell survival, blood vessel formation and cell migration than nonengineered ucMSCs (MSC-Exo).…”