Hepatocellular carcinoma (HCC) is strongly associated with metabolic dysregulations/deregulations and hyperglycemia is a common metabolic disturbance in metabolic diseases. Hyperglycemia is defined to promote epithelial to mesenchymal transition (EMT) of cancer cells in various cancers but its molecular contribution to HCC progression and aggressiveness is relatively unclear. In this study, we analyzed the molecular mechanisms behind the hyperglycemia-induced EMT in HCC cell lines. Here, we report that high glucose promotes EMT through activating c-Met receptor tyrosine kinase via promoting its ligand-independent homodimerization. c-Met activation is critical for high glucose induced acquisition of mesenchymal phenotype, survival under high glucose stress and reprogramming of cellular metabolism by modulating glucose metabolism gene expression to promote aggressiveness in HCC cells. The crucial role of c-Met in high glucose induced EMT and aggressiveness may be the potential link between metabolic syndrome-related hepatocarcinogenesis and/or HCC progression. Considering c-Met inhibition in hyperglycemic patients would be an important complementary strategy for therapy that favors sensitization of HCC cells to therapeutics.
Bibliographical noteFunding Information:
We thank Prof. Dr. Mehmet Ozturk for providing HCC cells, Izmir Biomedicine and Genome Center for establishment of required technical and instrumental infrastructure for this study, Prof. Dr. Jan-Wilhelm Kornfeld and Dr. Matteo Oliverio for their support in Seahorse experiments and Dr. Yasemin Öztemur Islakoğlu for her kind contribution to bioinformatic data analysis. This research was funded by “Scientific and Technological Research Council of Turkey (TUBITAK)” with the grant number of “114S359”.
© 2021, The Author(s).