Stiffer Matrix Accelerates Migration of Hepatocellular Carcinoma Cells through Enhanced Aerobic Glycolysis Via the MAPK-YAP Signaling

Abstract

Increased extracellular matrix (ECM) stiffness and metabolic reprogramming of cancer cells are two fundamental mediators of tumor progression, including hepatocellular carcinoma (HCC). Yet, the correlation between ECM stiffness and excessive aerobic glycolysis in promoting the development of HCC remains unknown. Here, we demonstrated that stiffer ECM promotes HCC cell migration depending on their accelerated aerobic glycolysis. Our results also indicated that stiffer ECM-induced YAP activation plays a major role in promoting aerobic glycolysis of HCC cells. Moreover, we showed that JNK and p38 MAPK signaling are critical for mediating YAP activation in HCC cells. Together, our findings established that the MAPK-YAP signaling cascade that act as a mechanotransduction pathway is essential for promoting HCC cell aerobic glycolysis and migration in response to ECM stiffness.

Extracellular Matrix Stiffness: New Areas Affecting Cell Metabolism

“…Previous studies have also shown that stiffness upregulates YAP/TAZ expression in various types of cells ( 24 , 25 , 29 – 32 ), such as hepatocellular carcinoma ( 25 ), hepatic stellate cells ( 33 ) and pulmonary artery endothelial cells ( 30 ). Consequently, this YAP/TAZ-mediated upregulation promotes uptake and utilization of cellular glucose, increases glycolysis, and influences glycogenolysis.…”

“…The mechanisms through which ECM stiffness upregulates YAP/TAZ are diverse, and may be regulated differently across different cell types. Generally, these mechanisms are broadly categorized as: (i) effect on cytoskeletal tension ( 24 ); (ii) effect on hyaluronic acid (HA) receptor CD44 ( 16 ); (iii) activation on the MAPK signaling cascade in hepatic cancer cells ( 25 ); (iv) ECM stiffness can affect cellular metabolism through integrin (discussed in a later section), and it has been reported that integrin affects cellular metabolism through YAP/TAZ ( 26 ). However, it is unclear whether ECM stiffness can activate YAP/TAZ through integrin.…”

Elevated expression of FREM1 in breast cancer indicates favorable prognosis and high‐level immune infiltration status

“…[6][7][8][9] Under physiological circumstances, FREM1 is widely expressed in epithelial-mesenchymal interaction and epidermal remodeling areas, for example, hair follicles, sensory vibrissae, teeth, footpads, and breast tissue. 10 Growing studies have shown that ECM-related proteins may modulate the migration and invasion of cancer cells through related signaling pathways, such as β1-integrin-Src-EGFR, 11 MAPK-YAP, 12 and PI3K-AKT signaling. 13 More importantly, the deposition, reconstruction, and cross-linking of ECM can reprogram the local microenvironment and regulate the pro-and antitumor immune responses upon the stimulation of different ECM-related proteins.…”

Mapping the Metabolic Networks of Tumor Cells and Cancer-Associated Fibroblasts

“…In hepatocellular carcinoma, induced ECM stiffness activated YAP downstream of c-Jun N-terminal kinases (JNK) and p38. In turn YAP activation increased the glycolytic pathway and migration of cancer cells [ 54 ]. YAP/TAZ has also been found to promote cancer cell proliferation by upregulating deoxynucleotide synthesis and inhibiting RAS-induced senescence in cells.…”