PMID- 33710809 OWN - NLM STAT- Publisher LR - 20240222 IS - 2095-3941 (Print) IS - 2095-3941 (Linking) VI - 18 IP - 3 DP - 2021 Mar 12 TI - NEDD9 promotes cancer stemness by recruiting myeloid-derived suppressor cells via CXCL8 in esophageal squamous cell carcinoma. PG - 705-20 LID - j.issn.2095-3941.2020.0290 [pii] LID - 10.20892/j.issn.2095-3941.2020.0290 [doi] AB - 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. CI - Copyright (c) 2021 Cancer Biology & Medicine. FAU - Yue, Dongli AU - Yue D AD - Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. AD - Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. FAU - Liu, Shasha AU - Liu S AD - Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. FAU - Zhang, Tengfei AU - Zhang T AD - Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. AD - Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. FAU - Wang, Yong AU - Wang Y AD - Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing 100730, China. AD - Biomed Innovation Center, Yehoo Group, Shenzhen 518067, China. FAU - Qin, Guohui AU - Qin G AD - Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. FAU - Chen, Xinfeng AU - Chen X AD - Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. FAU - Zhang, Huanyu AU - Zhang H AD - Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. FAU - Wang, Dong AU - Wang D AD - Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. FAU - Huang, Dong AU - Huang D AD - Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. FAU - Wang, Feng AU - Wang F AD - Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. FAU - Wang, Liping AU - Wang L AD - Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. FAU - Zhao, Song AU - Zhao S AD - Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. FAU - Zhang, Yi AU - Zhang Y AUID- ORCID: 0000-0001-9861-4681 AD - Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. AD - Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. AD - School of Life Sciences, Zhengzhou University, Zhengzhou 450052, China. AD - Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou 450052, China. LA - eng GR - 81602599/National Natural Science Foundation of China/ GR - 31400752/National Natural Science Foundation of China/ GR - 81771781/National Natural Science Foundation of China/ GR - U1804281/National Natural Science Foundation of China/ GR - 2016YFC1303501/National Key Research and Development Program of China/ PT - Journal Article DEP - 20210312 PL - China TA - Cancer Biol Med JT - Cancer biology & medicine JID - 101588850 SB - IM PMC - PMC8330544 OTO - NOTNLM OT - C-X-C motif chemokine ligand 8 (CXCL8) OT - Esophageal squamous cell carcinoma (ESCC) OT - cancer stem cells (CSCs) OT - myeloid derived suppressor cells (MDSCs) OT - neural precursor cell expressed, developmentally downregulated 9 (NEDD9) COIS- No potential conflicts of interest are disclosed. EDAT- 2021/03/13 06:00 MHDA- 2021/03/13 06:00 PMCR- 2021/08/15 CRDT- 2021/03/12 13:05 PHST- 2021/03/12 13:05 [entrez] PHST- 2021/03/13 06:00 [pubmed] PHST- 2021/03/13 06:00 [medline] PHST- 2021/08/15 00:00 [pmc-release] AID - j.issn.2095-3941.2020.0290 [pii] AID - 10.20892/j.issn.2095-3941.2020.0290 [doi] PST - aheadofprint SO - Cancer Biol Med. 2021 Mar 12;18(3):705-20. doi: 10.20892/j.issn.2095-3941.2020.0290.