ENO1 Promotes OSCC Migration and Invasion by Orchestrating IL-6 Secretion from Macrophages via a Positive Feedback Loop

Abstract

Oral squamous cell carcinoma (OSCC) has a five-year survival rate of less than 50% due to its susceptibility to invasion and metastasis. Crosstalk between tumor cells and macrophages has been proven to play a critical role in tumor cell migration and invasion. However, the specific mechanisms by which tumor cells interact with macrophages have not been fully elucidated. This study sought to investigate the regulatory mechanism of tumor cell-derived alpha-enolase (ENO1) in the interaction between tumor cells and macrophages during OSCC progression. Small interfering RNA (siRNA) transfection and recombinant human ENO1 (rhENO1) stimulation were used to interfere with the interaction between tumor cells and macrophages. Our results showed that ENO1 was expressed higher in CAL27 cells than in HaCaT cells and regulated lactic acid release in CAL27 cells. Conditioned medium of macrophages (Macro-CM) significantly up-regulated the ENO1 mRNA expression and protein secretion in CAL27 cells. ENO1 promoted the migration and invasion of tumor cells by facilitating the epithelial–mesenchymal transition (EMT) through macrophages. ENO1 orchestrated the IL-6 secretion of macrophages via tumor cell-derived lactic acid and the paracrine ENO1/Toll-like receptor (TLR4) signaling pathway. In turn, IL-6 promoted the migration and invasion of tumor cells. Collectively, ENO1 promotes tumor cell migration and invasion by orchestrating IL-6 secretion of macrophages via a dual mechanism, thus forming a positive feedback loop to promote OSCC progression. ENO1 might be a promising therapeutic target which is expected to control OSCC progression.

Single-Cell Transcriptomic Profiling Unveils Critical Metabolic Alterations and Signatures in Progression of Atherosclerosis

“…New insights have shed light on the importance of metabolic and functional reprogramming in macrophages for AS progression [9]. Specially, researchers have linked the macrophage GLUL, LDHA, ENO1 as well as PGK1 to polarization, pro-inflammatory factors release and plaque vulnerability [50][51][52][53]. Our present study also pointed out that these genes are also involved in the regulation of metabolic shifts, and highly associated with inflammation.…”

Novel In Vitro Assay of the Effects of Kampo Medicines against Intra/Extracellular Advanced Glycation End-Products in Oral, Esophageal, and Gastric Epithelial Cells

“…RAGE is expressed on the surface of oral [ 17 ], esophageal [ 17 ], and gastric [ 41 ] epithelial cells, allowing extracellular AGEs to bind to and induce effects against these cells. TLR4 is also expressed in all three cell types [ 38 , 39 , 40 , 41 , 44 , 85 ]. In the investigation of the effects of extracellular AGEs via RAGE/TLR4 in these cells in vitro, digestion, absorption, and metabolization can be excluded, as discussed above, and an assessment of the effects of samples such as Kampo medicines against AGEs-RAGE/TLR4 combinations is, thus, practical ( Figure 4 ).…”

“…Therefore, we hypothesize that it should be possible to detect rapidly generated intracellular AGEs in these cells. The receptor for AGEs (RAGE) [ 17 , 18 , 37 , 38 , 39 ] and the toll-like receptor 4 (TLR4) [ 40 , 41 , 42 ] are expressed on the surface of the epithelial cells of interest. Extracellular AGEs (e.g., dietary [ 20 , 21 ] or in saliva and blood [ 43 , 44 ]) bind to RAGE and TLR4 and can cause cytotoxicity, such as inflammation [ 37 , 38 , 39 , 40 , 41 , 42 ].…”

“…The receptor for AGEs (RAGE) [ 17 , 18 , 37 , 38 , 39 ] and the toll-like receptor 4 (TLR4) [ 40 , 41 , 42 ] are expressed on the surface of the epithelial cells of interest. Extracellular AGEs (e.g., dietary [ 20 , 21 ] or in saliva and blood [ 43 , 44 ]) bind to RAGE and TLR4 and can cause cytotoxicity, such as inflammation [ 37 , 38 , 39 , 40 , 41 , 42 ]. Therefore, an in vitro assay using oral, esophageal, and gastric epithelial cells could assess the effects of samples such as Kampo medicines against the AGEs-RAGE/TLR4 combination.…”

Analysis of Crude, Diverse, and Multiple Advanced Glycation End-Product Patterns May Be Important and Beneficial

“…Notwithstanding, we have focused on the relationship between dietary AGEs and oral, esophageal, and gastric epithelial cells [ 1 ]. RAGE is expressed on oral [ 79 , 80 ], esophageal [ 81 ], and gastric epithelial cells [ 82 ], and TLR4 is expressed on oral [ 83 ], esophageal [ 84 ], and gastric epithelial cells [ 85 ]. Because these epithelial cell types are exposed to air and direct physical contact with dietary AGEs, the dietary AGEs-RAGE/TRL4 axis may appear.…”