SLC7A2 deficiency promotes hepatocellular carcinoma progression by enhancing recruitment of myeloid-derived suppressors cells

Suhong Xia,Wangdong Zhou,Dean Tian,Jingmei Liu,Mingyu Zhang,Kai Zhao,Jingwen Wu,Jiazhi Liao

doi:10.1038/s41419-021-03853-y

Abstract

The main reason for poor prognosis in hepatocellular carcinoma (HCC) patients is high metastasis and recurrence. Cancer progression depends on a tumor-supportive microenvironment. Therefore, illustrating the mechanisms of tumor immunity in underlying HCC metastasis is essential. Here, we report a novel role of solute carrier family 7 member 2 (SLC7A2), a member of the solute carrier family, in HCC metastasis. The reduction of SLC7A2 was an independent and significant risk factor for the survival of HCC patients. Upregulation of SLC7A2 decreased HCC invasion and metastasis, whereas downregulation of SLC7A2 promoted HCC invasion and metastasis. We further found that deficient SLC7A2 medicated the upregulation of CXCL1 through PI3K/Akt/NF-kκB pathway to recruit myeloid-derived suppressor cells (MDSCs), exerting tumor immunosuppressive effect. Moreover, we found that G9a-mediated di-methylation of H3K9 (H3K9me2) silenced the expression of SLC7A2 to suppress HCC metastasis and immune escape. In conclusion, G9a-mediated silencing of SLC7A2 exerts unexpected functions in cancer metastasis by fostering a tumor-supportive microenvironment through CXCL1 secretion and MDSCs recruitment. Thus, SLC7A2 may provide new mechanistic insight into the cancer-promoting property of MDSCs.

Highlights

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide[1]
Patients with overexpression of Myeloid-derived suppressor cells (MDSCs) infiltration demonstrated a shorter overall survival than those with downregulated MDSC infiltration (Fig. 3J). These findings demonstrated that deficiency of SLC7A2 upregulates CXCL1 and induces MDSC chemotaxis, MDSC infiltration may indicate a poorer prognosis
We intended to clear the function of the tumor-supportive microenvironment in hepatocellular carcinoma (HCC) metastasis

Summary

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide[1]. A growing number of strategies have been achieved in the prevention, diagnosis, and treatment of HCC, such as surgical resection and a series of drugs including multikinase and immune checkpoint inhibitors for HCC2. Immune checkpoint inhibitors including nivolumab and pembrolizumab are emerging in the treatment of malignant tumors including HCC but only a fraction of HCC patients show a positive effect[6]. Emerging evidence suggests that immune evasion is one of the major hallmarks of cancer[7]. It is well recognized that HCC is usually preceded by liver damage and chronic inflammatory stimulation, and is accompanied by infiltration of many immune cells[9,10]. Often accompanied by the activation of immune checkpoint signals such as programmed cell death receptor 1 (PD-1) and its ligand

Methods

Results

Conclusion