ECT2 overexpression promotes the polarization of tumor-associated macrophages in hepatocellular carcinoma via the ECT2/PLK1/PTEN pathway

Dafeng Xu,Mingwei Xie,Shixun Lin,Jincai Wu,Liang Chen,Zhensheng Zhang,Cheng Chen,Rong Tang,Xiangxiang Luo,Jiacheng Chen,Jinfang Zheng,Yu Wang

doi:10.1038/s41419-021-03450-z

Abstract

Hepatocellular carcinoma (HCC) is a common high-mortality cancer, mainly due to diagnostic difficulties during its early clinical stages. In this study, we aimed to identify genes that are important for HCC diagnosis and treatment, and we investigated the underlying mechanism of prognostic differences. Differentially expressed genes (DEGs) were identified by using the limma package, and receiver operating characteristic curve analysis was performed to identify diagnostic markers for HCC. Bioinformatics and clinical specimens were used to assess epithelial cell transforming 2 (ECT2) in terms of expression, prognostic value, pathways, and immune correlations. In vitro experiments were used to investigate the underlying mechanism and function of ECT2, and the results were confirmed through in vivo experiments. The integrated analysis revealed 53 upregulated DEGs, and one candidate biomarker for diagnosis (ECT2) was detected. High expression of ECT2 was found to be an independent prognostic risk factor for HCC. ECT2 expression showed a strong correlation with tumor-associated macrophages. We found that ECT2 overexpression increased the migration and proliferation of HCC cells. It also promoted the expression of PLK1, which subsequently interacted with PTEN and interfered with its nuclear translocation, ultimately enhancing aerobic glycolysis and promoting M2 macrophage polarization. M2 macrophages suppress the functions of NK cells and T cells, and this was confirmed in the in vivo experiments. Overall, ECT2 may promote the polarization of M2 macrophages by enhancing aerobic glycolysis and suppressing the functions of immune cells. ECT2 could serve as a candidate diagnostic and prognostic biomarker for HCC.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most common cancer and has the third highest cancer-related death rate[1,2]
Upregulated Differentially expressed genes (DEGs) were detected in the three cohorts of GSE76311, GSE101685, and GSE101728, with a log[2] fold change (FC) value > 1 and a modified p value < 0.05 as the screening criteria
The impaired proliferation of HCC cells induced by epithelial cell transformation sequence 2 (ECT2) knockdown was partially rescued after PTEN downregulation (Fig. 5F). These results suggested that PLK1 interacted with PTEN and inhibited PTEN nuclear translocation, and the metabolism and proliferation function of ECT2 was dependent on PTEN expression

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer and has the third highest cancer-related death rate[1,2]. The epithelial cell transformation sequence 2 (ECT2) protein is an exchange factor in the Rho band[6]. The activation of the ECT2/Rho pathway may promote the progression of several tumors[7]. ECT2 may promote the progression of human HCC by regulating the Rho/ ERK signaling axis[8,9,10]. ECT2 plays a tumorpromoting role in a number of other cancers, such as non-small cell lung cancer and breast cancer[11,12,13,14]. The underlying mechanism responsible for the function of ECT2 has remained unclear

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