ENO2 promotes anoikis resistance in anaplastic thyroid cancer by maintaining redox homeostasis.

BACKGROUND: Anoikis presents a significant barrier in the metastasis of cancer. As the most aggressive type of thyroid cancer, anaplastic thyroid cancer (ATC) exhibits a high risk of metastasis and is characterized by high mortality. Therefore, investigating the molecular mechanisms of anoikis resistance in ATC is important for devising therapeutic targets in clinical research.

METHODS: Differentially Expressed Genes were screened in ATC cells under attached and detached culture conditions with RNA-seq. Investigate the impact of enolase 2 (ENO2) on apoptosis and spheroid formation by gain and loss of function. Changes of reactive oxygen species (ROS), glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) were detected to assess redox balance. The transcriptional regulatory role of signal transducer and activator of transcription 1 (STAT1) on ENO2 was validated through Dual-Luciferase Reporter Gene Assay. Explore the impact of ENO2 expression on the formation of lung metastases in nude mice.

RESULTS: We found that the glycolysis process was activated in detached ATC cells. Several genes in the glycolysis process, particularly ENO2 , a member of the enolase superfamily was upregulated in ATC cells cultured in suspension. The upregulation of ENO2 enabled the maintenance of redox balance by supplying GSH and NADPH, thereby preventing cells from undergoing anoikis. In terms of mechanism, the expression of STAT1 was enhanced in anoikis resistance cells, which in turn positively regulated the expression of ENO2. In vivo , ENO2-suppressed ATC cells resulted in a significantly lower rate of lung colonization compared to control ATC cells.

CONCLUSIONS: Stable expression of ENO2 and the maintenance of redox balance played a pivotal role in facilitating anoikis resistance of ATC.