NEDD9 promotes cancer stemness by recruiting myeloidderived suppressor cells <i>via</i> CXCL8 in esophageal squamous cell carcinoma

癌症研究 癌症干细胞 转移 医学 生物 干细胞 内科学 癌症 细胞生物学
作者
Dongli Yue,Shasha Liu,Tengfei Zhang,Yong Wang,Guohui Qin,Xinfeng Chen,Huanyu Zhang,Dong Wang,Lan Huang,Feng Wang,Li Wang,Song Zhao,Yi Zhang
出处
期刊:Cancer biology and medicine [Cancer Biology and Medicine]
卷期号:18 (3): 705-720 被引量:20
标识
DOI:10.20892/j.issn.2095-3941.2020.0290
摘要

Objective:

Esophageal squamous cell carcinoma (ESCC) has high morbidity and mortality rates worldwide. Cancer stem cells (CSCs) may cause tumor initiation, metastasis, and recurrence and are also responsible for chemotherapy and radiotherapy failures. Myeloid-derived suppressor cells (MDSCs), in contrast, are known to be involved in mediating immunosuppression. Here, we aimed to investigate the mechanisms of interaction of CSCs and MDSCs in the tumor microenvironment.

Methods:

ESCC tissues and cell lines were evaluated. Neural precursor cell expressed, developmentally downregulated 9 (NEDD9) was knocked down and overexpressed by lentiviral transfection. Quantitative PCR, Western blot, immunohistochemistry, cell invasion, flow cytometry, cell sorting, multiplex chemokine profiling, and tumor growth analyses were performed.

Results:

Microarray analysis revealed 10 upregulated genes in esophageal CSCs. Only NEDD9 was upregulated in CSCs using the sphere-forming method. NEDD9 expression was correlated with tumor invasion (P = 0.0218), differentiation (P = 0.0153), and poor prognosis (P = 0.0373). Additionally, NEDD9 was required to maintain the stem-like phenotype. Screening of chemokine expression in ESCC cells with NEDD9 overexpression and knockdown showed that NEDD9 regulated C-X-C motif chemokine ligand 8 (CXCL8) expression via the ERK pathway. CXCL8 mediated the recruitment of MDSCs induced by NEDD9 in vitro and in vivo. MDSCs promoted the stemness of ESCC cells through NEDD9 via the Notch pathway.

Conclusions:

As a marker of ESCC, NEDD9 maintained the stemness of ESCC cells and regulated CXCL8 through the ERK pathway to recruit MDSCs into the tumor, suggesting NEDD9 as a therapeutic target and novel prognostic marker for ESCC.
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