Exosome-derived ENO1 regulates integrin \u03b16\u03b24 expression and promotes hepatocellular carcinoma growth and metastasis

Keqiu Jiang,Qi Wang,Chengye Wang,Liming Wang,Zhenming Gao,Zeli Yin,Rui Liang,Chengyong Dong,Junlin Zhang,Jiakai Mao,Rui Li

doi:10.1038/s41419-020-03179-1

Abstract

Alpha-enolase (ENO1) has been found to be dysregulated in several human malignancies, including hepatocellular carcinoma (HCC). Although the role of ENO1 as a glycolytic enzyme in HCC cells has been well characterized, little is known about the other roles of ENO1, especially exosome-derived ENO1, in regulating HCC progression. Here, we demonstrated that ENO1 is frequently upregulated in HCC cells or tissues, with even higher expression in highly metastatic HCC cells or metastatic tissues as well as in exosomes derived from highly metastatic sources. Moreover, ENO1 expression is associated with the tumor-node-metastasis (TNM) stage, differentiation grade and poor prognosis in HCC patients. Surprisingly, ENO1 can be transferred between HCC cells via exosome-mediated crosstalk, exhibiting an effect similar to that of ENO1 overexpression in HCC cells, which promoted the growth and metastasis of HCC cells with low ENO1 expression by upregulating integrin α6β4 expression and activating the FAK/Src-p38MAPK pathway. In summary, our data suggest that exosome-derived ENO1 is essential to promoting HCC growth, metastasis, and further patient deterioration. The findings from this study implicate a novel biomarker for the clinical evaluation of HCC progression, especially the prediction of HCC metastatic risk.

Highlights

Liver cancer is the fourth most common cause of cancer-related death and is the second most lethal type of cancer, with a 5-year survival rate of 18%1
To demonstrate the effect of highly metastatic Hepatocellular carcinoma (HCC) cellderived exosome education, we first evaluated the malignant phenotypes of three HCC cell lines with different metastatic potential constructed based on the same parental cell line by the Liver Cancer Institute & Zhongshan Hospital of Fudan University[35,36,37,38]
The diversity of HCC cells is the key factor in the treatment failure and death of HCC patients

Summary

Introduction

Liver cancer is the fourth most common cause of cancer-related death and is the second most lethal type of cancer, with a 5-year survival rate of 18%1. Hepatocellular carcinoma (HCC), a main type of primary liver cancer, usually occurs in patients with hepatitis virus infection, alcohol abuse, metabolic syndrome or obesity. Because of the high incidence of metastasis, systemic treatment is highly recommended for a large proportion of HCC. Exosomes (50–150 nm in diameter), a class of extracellular vesicles, are nanosized vesicles surrounded by bimolecular lipid membranes and are formed by a series of precise regulatory processes, such as the “endocytosisfusion-efflux” process. Exosomes usually contain a variety of biomolecules, including proteins, nucleic acids, lipids, and even viruses[3,4]. The role of exosomes and their contents as potential contributors to oncogenesis and tumor metastasis is a current research focus.

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