4.6 Article

NEDD9 promotes cancer stemness by recruiting myeloid-derived suppressor cells via CXCL8 in esophageal squamous cell carcinoma

Journal

CANCER BIOLOGY & MEDICINE
Volume 18, Issue 3, Pages 705-+

Publisher

CHINA ANTI-CANCER ASSOC
DOI: 10.20892/j.issn.2095-3941.2020.0290

Keywords

Esophageal squamous cell carcinoma (ESCC); cancer stem cells (CSCs); neural precursor cell expressed; developmentally downreg-ulated 9 (NEDD9); myeloid derived suppressor cells (MDSCs); C-X-C motif chemokine ligand 8 (CXCL8)

Funding

  1. National Natural Science Foundation of China [81602599, 31400752, 81771781, U1804281]
  2. National Key Research and Development Program of China [2016YFC1303501]

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This study identified NEDD9 as a marker for ESCC stem cells, involved in regulating the stemness of ESCC cells and recruiting MDSCs into the tumor microenvironment via the ERK pathway-mediated CXCL8 expression. MDSCs promote the stemness of ESCC cells through the Notch pathway in a NEDD9-dependent manner, suggesting NEDD9 as a potential therapeutic target and novel prognostic marker for ESCC.
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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