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

Qiu-Ping Liu,Yang Ju,Guan-Bin Song,Bin Deng,Qing Luo

doi:10.3390/cancers12020490

Qiu-Ping Liu, Yang Ju + Show 3 more

Open Access

https://doi.org/10.3390/cancers12020490

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Journal: Cancers	Publication Date: Feb 19, 2020
Citations: 62	License type: CC BY 4.0

Affiliation: Chongqing University, Nagoya University

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.

Highlights

Tumors generate physical forces during tumorigenesis, including solid stress, interstitial fluid pressure and extracellular matrix (ECM) stiffness [1]
The migration ability of Hepatocellular carcinoma (HCC) cells treated with JNK and p38 kinase inhibitors or knockdown of Yes-associated protein (YAP) was detected by using transwell assay, the result showed that these two inhibitors and knockdown of YAP all downregulated the migration ability of HCC cells on stiffer matrix. These two inhibitors restored the migration ability of HCC cells cultured on stiffer matrix to the same level as that on soft matrix, which is consistent with the effect of YAP-siRNAs (Figure 6g). These results demonstrated that the regulation of YAP activation by ECM stiffness is depending on JNK and p38 mitogen-activated protein kinase (MAPK) signaling cascades and ECM stiffness regulates the migration of HCC cells through MAPK-YAP mechanotransduction
We identified a MAPK-dependent regulatory network involving YAP that controls aerobic glycolysis during HCC cell migration caused by ECM stiffening (Figure 7)

Summary

Introduction

Tumors generate physical forces during tumorigenesis, including solid stress, interstitial fluid pressure and extracellular matrix (ECM) stiffness [1]. These physical forces are continuously applied to cancer cells within tumor tissues and dynamically modify their behaviors [2,3]. Tumor mechanics, tissue stiffness in particular, has emerged as an important factor that correlates with cancer progression and aggression [4]. Human breast cancer invasion and aggression were shown to correlate with ECM stiffening [5]. Hepatocellular carcinoma (HCC) as one of the commonest human solid tumors has the feature of increased stiffness of the liver tissue, accompanied with abnormal angiogenesis.

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