A new risk model comprising genes highly correlated with CD133 identifies different tumor-immune microenvironment subtypes impacting prognosis in hepatocellular carcinoma.

Huajian Yu,Hongyu Pan,Ming Yao,Miaoxin Zhu,Xiaoqiang Zhu,Lei Sun,Hechun Lin,Fangyu Zhao,Mingxia Yan,Wenjun Chai

doi:10.18632/aging.103409

Abstract

The existence of cancer stem cells (CSCs), marked by CD133, is the primary cause of death in hepatocellular carcinoma (HCC). Here, we generated a new risk model comprising the signatures of four genes highly correlated with CD133 (CD133(hi)) that help improve survival in HCC. Three datasets were used to identify the differential CD133(hi) genes by comparing sorted CD133+ liver CSCs and CD133- differentiated counterparts. Univariate analysis was used to screen significantly differential CD133(hi) genes associated with overall survival in the training dataset, which were used for risk model construction. High-risk patients were strongly associated with poor survival by Kaplan-Meier survival analysis in both the training and validation datasets. Clinical stratification analyses further demonstrated that the risk factors acted as independent factors and that high-risk patients were characterized by more aggressive cancer features. Functional enrichment analyses performed by gene set enrichment analysis (GSEA) and the Database for Annotation, Visualization and Integrated Discovery (DAVID) revealed that high-risk patients showed the disturbance of immune hepatic homeostasis involving aberrant immune cells, including macrophages and T and B cells, and an abnormal inflammatory response including the IL6/Jak/STAT3 pathway and TNF signaling pathway. In conclusion, our constructed CD133(hi) gene risk model provides a resource for understanding the role of CD133+ CSCs in the progression of HCC in terms of tumor-immune interactions.

Highlights

Hepatocellular carcinoma (HCC) is a very deadly and aggressive disease and represents the second leading cause of cancer-related mortality worldwide [1]
The hepatocellular carcinoma (HCC) microenvironment is characterized by the presence of endothelial cells, hepatic stellate cells, tumor-associated macrophages (TAMs), regulatory T cells, cancer-associated fibroblasts, and Cancer stem cells (CSCs) mixed within an excessive accumulation of extracellular matrix (ECM)
The development of effective treatments for HCC has been hindered by the enhanced expression of the CSCs marker CD133, which has been reported to be aberrantly regulated by abnormal inflammatory factors, such as IL-6/STAT3, and effector immune cells

Summary

Introduction

Hepatocellular carcinoma (HCC) is a very deadly and aggressive disease and represents the second leading cause of cancer-related mortality worldwide [1]. CD133 has been shown to be a marker of a liver CSC subset, and CD133+ HCC www.aging-us.com cells are well known for their role in frequent relapse, drug resistance, tumor initiation, sustained self-renewal, differentiation and phenocopying of the original tumor [4,5,6]. The HCC microenvironment is characterized by the presence of endothelial cells, hepatic stellate cells, tumor-associated macrophages (TAMs), regulatory T cells, cancer-associated fibroblasts, and CSCs mixed within an excessive accumulation of extracellular matrix (ECM). This microenvironment acts as a fertile environment to grow cancer seeds [7]. A previous report demonstrated that therapeutic components that target TME by downregulating the expression of CSC markers, including CD133, showed evident antitumor effects [9]

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