CXCL3 contributes to CD133(+) CSCs maintenance and forms a positive feedback regulation loop with CD133 in HCC via Erk1/2 phosphorylation.

Lin Zhang,Guoping Jiang,Taoyang Chen,Haiyang Xie,Ying Cui,Hua Tian,Ming Yao,Lixing Zhang,Hong Li,Jinjun Li,Fangyu Zhao,Chao Ge

doi:10.1038/srep27426

Abstract

Although the chemotactic cytokine CXCL3 is thought to play an important role in tumor initiation and invasion, little is known about its function in hepatocellular carcinoma (HCC). In our previous study, we found that Ikaros inhibited CD133 expression via the MAPK pathway in HCC. Here, we showed that Ikaros may indirectly down-regulate CXCL3 expression in HCC cells, which leads to better outcomes in patients with CD133+ cancer stem cell (CSC) populations. CD133 overexpression induced CXCL3 expression, and silencing of CD133 down-regulated CXCL3 in HCC cells. Knockdown of CXCL3 inhibited CD133+ HCC CSCs’ self-renewal and tumorigenesis. The serum CXCL3 level was higher in HCC patients’ samples than that in healthy individual. HCC patients with higher CXCL3 expression displayed a poor prognosis, and a high level of CXCL3 was significantly associated with vascular invasion and tumor capsule formation. Exogenous CXCL3 induced Erk1/2 and ETS1 phosphorylation and promoted CD133 expression, indicating a positive feedback loop between CXCL3 and CD133 gene expression in HCC cells via Erk1/2 activation. Together, our findings indicated that CXCL3 might be a potent therapeutic target for HCC.

Highlights

Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and the third leading cause of cancer-related death worldwide[1]
Our research showed that CXCL3 was significantly overexpressed in the CD133+ cancer stem cell (CSC) population compared with its corresponding CD133− non-CSC population, and CXCL3 expression was positively correlated with CD133 expression in hepatocellular carcinoma (HCC)
We reported that Ikaros inhibited the expression of CD133 via direct binding to the CD133 P1 promoter and repressed the tumorigenic and self-renewal capacity of CD133+ CSCs

Summary

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and the third leading cause of cancer-related death worldwide[1]. Our previous studies have shown that CD133+ HCC cells are of high tumorigenicity and chemotherapy resistance, with high expression of a number of stemness genes, and these cells could be induced to differentiate by exogenous BMP4 treatment, demonstrating that CD133 is a CSC marker in HCC6–8. Chemokines and their G-protein-coupled receptors were originally reported to mediate different pro- and anti-inflammatory responses[9]. Many chemokines promote malignancy, CX3CL1 is believed to inhibit HCC tumor growth and recurrence[14,15], suggesting that different chemokines may exert distinct functions in the same cancer. We found that CXCL3 may be involved in a feedback loop regulating CD133 expression via the MAPK/ETS1 pathway in HCC and that HCC patients with higher CXCL3 expression levels displayed a poor prognosis

Methods

Results

Conclusion