NR2F1 contributes to cancer cell dormancy, invasion and metastasis of salivary adenoid cystic carcinoma by activating CXCL12/CXCR4 pathway
NR2F1 contributes to cancer cell dormancy, invasion and metastasis of salivary adenoid cystic carcinoma by activating CXCL12/CXCR4 pathway
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NR2F1通过激活CXCL12/CXCR4通路促进唾液腺腺样囊性癌癌细胞休眠、侵袭和转移
DOI：
10.1186/s12885-019-5925-5
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发表时间：
2019-07-29
期刊：
影响因子：
3.8
通讯作者：
Tang, Ya-ling
中科院分区：
文献类型：
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作者：
Gao, Xiao-lei;Zheng, Min;Tang, Ya-ling
研究背景涎腺腺样囊性癌（salivary adenoid cystic carcinoma，SACC）在原发肿瘤切除后经治疗后可复发，可保持无临床症状和休眠状态10- 15年。NR 2F 1在多种恶性肿瘤中具有调节肿瘤细胞休眠的作用，对肿瘤的复发和转移有潜在的影响。方法采用免疫组化（IHC）和末端脱氧核苷酸转移酶介导的dUTP缺口标记法（TUNEL）检测59例SACC中NR 2F 1、Ki-67的表达。采用Fisher精确检验分析SACC中NR 2F 1的表达与临床病理参数的关系。在体外，分别转染NR 2F 1和敲低NR 2F 1的SACC细胞系。CCK-8、流式细胞术、创伤愈合实验和transwell侵袭实验分别检测SACC细胞增殖、凋亡、细胞周期、迁移和侵袭能力。利用染色质免疫沉淀（ChIP）分析来证明NR 2F 1通过CXCL 12/CXCR 4轴在SACC侵袭中的潜在作用。结果59例SACC中NR 2F 1阳性表达率为23.73%（14/59），低于正常涎腺组织中的60%（6/10）。NR 2F 1与SACC的转移、复发和休眠有关。转染NR 2F 1的SACC细胞保持休眠状态，并增强侵袭和转移。NR 2F 1过表达后，siRNA敲除NR 2F 1可使细胞增殖恢复，G2/M期细胞数减少，迁移和侵袭能力降低。结论NR 2F 1可能通过调节CXCL 12/CXCR 4信号通路调节肿瘤细胞的休眠状态，从而促进SACC的复发和转移。
BackgroundSalivary adenoid cystic carcinoma (SACC) can recur after removal of the primary tumor and treatment, where they can keep no clinical symptoms and dormant state for 10-15years. NR2F1 has been demonstrated to regulate the tumor cell dormancy in various malignant tumors and has a potential impact on recurrence and metastasis of carcinoma. However, the role and significance of NR2F1 in SACC dormancy still remain unknown.MethodsA total number of 59 patients with a diagnosis of SACC were included to detected expression of NR2F1, Ki-67 by immunohistochemical (IHC) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick and labeling (TUNEL). Fisher's exact test was used to examine the NR2F1 expression and clinicopathologic parameters of SACC. In vitro, SACC cell lines were transfected NR2F1 and knockdown NR2F1 respectively. CCK-8, flow cytometry, wound healing assay and transwell invasion determined SACC cell proliferation, apoptosis, cell cycle, migration and invasion respectively. Chromatin immunoprecipitation (ChIP) assays were utilized to demonstrate the potential role of NR2F1 in SACC invasion via CXCL12/CXCR4 axis. In vivo, xenografts of nude mice via subcutaneous injection or tail vein injection were used to testify the results in vitro.ResultsAmong the 59 patients with SACC, 23.73% (14/59) were positive to NR2F1 expression, a lower rate of expression compared with 60% (6/10) in normal salivary gland samples. NR2F1 was correlated with metastasis, relapse and dormancy of SACC. SACC cells with transfected NR2F1 remained dormant, as well as enhanced invasion and metastasis. Knockdown of NR2F1 via siRNA after NR2F1 overexpression restored the proliferation and the cell number in G2/M phases, and reduced the abilities of migration and invasion. In addition, NR2F1 promoted the expression of CXCL12 and CXCR4, and overexpression of CXCL12 at least partly rescued the proliferation, migration, and invasion activities induced by NR2F1 silencing.ConclusionsNR2F1 may be an underlying mechanism of SACC recurrence and metastasis via regulating tumor cell dormancy through CXCL12/CXCR4 pathway.