Macrophage migration inhibitory factor promotes tumor aggressiveness of esophageal squamous cell carcinoma via activation of Akt and inactivation of GSK3β.
The pleiotropic pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF), represents an important link between chronic inflammation and tumorigenesis. Although accumulating evidence demonstrates that MIF overexpression is implicated in the development and progression of multiple cancers, including esophageal squamous cell carcinoma (ESCC), the molecular mechanisms underlying its tumor-promoting roles in ESCC remain unclear. In the present study, we observed that MIF is overexpressed in ESCC and correlated significantly with lymph node metastasis, advanced clinical stage, and poor survival of ESCC. MIF knockdown attenuated the proliferation, migration, and invasion of ESCC cells in vitro and in vivo. Moreover, blockage of MIF expression decreased the activation of the Akt, MEK/ERK, and NF-κB pathways and enhanced sensitivity to apoptosis. Meanwhile, repression of MIF expression resulted in activation of glycogen synthase kinase 3 beta (GSK3β) and subsequent decrease of active β-catenin, as well as its downstream targets including cyclin D1, matrix metalloproteinase (MMP)-7, c-myc, and c-Jun. Collectively, our results provided mechanistic insights into the tumor-promoting role of MIF in ESCC, and suggested that MIF represents a potential therapeutic target for treatment of ESCC.
['Liu|Rui-Min|RM|', 'Sun|Dan-Ni|DN|', 'Jiao|Ye-Lin|YL|', 'Wang|Pan|P|', 'Zhang|Juan|J|', 'Wang|Ming|M|', 'Ma|Jin|J|', 'Sun|Man|M|', 'Gu|Bian-Li|BL|', 'Chen|Pan|P|', 'Liu|Ke|K|', 'Ma|Heng|H|', 'Gao|She-Gan|SG|', 'Ma|Yuan-Fang|YF|', 'Qi|Yi-Jun|YJ|']
D000328:Adult D000368:Aged D000818:Animals D017209:Apoptosis D002294:Carcinoma, Squamous Cell D045744:Cell Line, Tumor D058750:Epithelial-Mesenchymal Transition D004938:Esophageal Neoplasms D000077277:Esophageal Squamous Cell Carcinoma D005260:Female D000071679:Glycogen Synthase Kinase 3 beta D006801:Humans D008263:Macrophage Migration-Inhibitory Factors D008297:Male D051379:Mice D008875:Middle Aged D009361:Neoplasm Invasiveness D009367:Neoplasm Staging D051057:Proto-Oncogene Proteins c-akt
Esophageal squamous cell carcinoma GSK3β MIF Cancer progression Prognosis