Macrophage migration inhibitory factor regulatesproliferation of gastric cancer cellsvia the PI3K/Akt pathway

Abstract

AIM:To investigate the effects of macrophage migration inhibitory factor (MIF) on proliferation of human gastric cancer MGC-803 cells and expression of cyclin D1 and p27Kip1 in them, and further determine whether the effects are related to the PI3K/Akt signal transduction pathway. METHODS:Gastric cancer MGC-803 cells were cultured and then treated with 50 μg/L recombinant human MIF (rhMIF) with and without a PI3K inhibitor, LY294002 (25 μmol/L). MTT assay was used to detect the proliferation of MGC-803 cells. Cell cycle was detected by flow cytometry. Expression of cyclin D1 and p27Kip1 mRNA was by reverse transcription-polymerase chain reaction. Protein expression of phosphorylated Akt (p-Akt), Akt, cyclin D1 and p27Kip1 was examined by immunocytochemistry and Western blotting.RESULTS: rhMIF significantly stimulated the proliferation of MGC-803 cells and cell cycle progression from G1 phase to S phase in a concentration-and time-dependent manner. After the MGC-803 cells were treated with rhMIF for 24 h, the expression of cyclin D1 was significantly up-regulated compared with the cells not treated with rhMIF at both mRNA and protein levels (0.97 ± 0.02 vs 0.74 ± 0.01, P = 0.002; 0.98 ± 0.05 vs 0.69 ± 0.04, P = 0.003). The p27Kip1 was downregulated but only statistically significant at the protein level. rhMIF significantly increased the expression of p-Akt, which reached the peak at 30 min, but did not affect the expression of Akt. However, LY294002 inhibited all the effects of rhMIF. CONCLUSION:Macrophage MIF increases the proliferation of gastric cancer cells, induces the expression of cyclin D1 at the transcriptional level and inhibits the expression of p27Kip1 at the post-transcriptional level via the PI3K/Akt pathway.

Cyclooxygenase-2 in tumor-associated macrophages promotes metastatic potential of breast cancer cells through Akt pathway

“…Moreover, the activation of Akt axis is also emerging as a central feature of EMT 49. Studies including our previous study demonstrated that TAMs induced the activation of Akt pathway in cancer cells, as products secreted from TAMs served as the potential activators of this pathway 11,50,51. Here, we further identified that the Akt pathway played a critical role in COX-2 + TAMs-induced cancer cell invasion by regulating MMP-9 and EMT process.…”

Chronic Macrophage Migration Inhibitory Factor Exposure Induces Mesenchymal Epithelial Transition and Promotes Gastric and Colon Cancers

“…Continuing studies suggested that CD74 couples with CXCR2 or CXCR4 to induce signaling events [18], [35]. Further studies also found a role for the Akt pathway in general cell survival studies [36], [37]. Additionally, one recent study showed that MIF regulates Akt signaling in a hypoxic environment to activate mesenchymal stem cells to support proliferation [38].…”

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

“…In addition, MIF may enhance cell proliferation by activating not only the ERK1/2 pathway but also the phosphoinositide 3-kinase/AKT pathway. Notably, in a previous study, immunocytochemistry and western blotting revealed that the addition of recombinant human MIF to the cell medium of the gastric cancer MGC-803 cell line resulted in increased AKT phosphorylation (37).…”