Hunan Provincial Cancer Hospital and Tumor Hospital Affiliated to Xiangya Medical School, Central South University, Changsha, Hunan, 410013, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
Department of Pathology, Affiliated Hospital of Jining Medical University, Jining, 272029, Shandong, China.
Cancer Lett. 2019 Feb 1;442:1-14. doi: 10.1016/j.canlet.2018.10.036. Epub 2018 Oct 28.
Nasopharyngeal carcinoma (NPC) is a unique subtype of head and neck squamous carcinoma that is notorious for its high metastatic potential. In this study, we reported that FOXA1 protein was decreased in NPC cells. Loss of FOXA1 is associated with lymph node metastasis and poor prognosis. Silencing FOXA1 in NP69 and C666-1 NPC cells accelerated cell proliferation and migration, while re-expression of FOXA1 has opposite effects. Microarray and RNA-seq analysis revealed that re-expression of FOXA1 in NPC cells reprogrammed the TGF-β-stimulated transcription program, which is characterized by promotion of TGF-β-inducible tumor-suppressive targets but repression of TGF-β-inducible oncogenes expression in NPC cells, leading to restoration of NPC cell sensitivity to TGF-β's growth-inhibitory effect. BAMBI, a TGF-β responsive tumor suppressor, was induced by FOXA1 in NPC cells. FOXA1 binding on the BAMBI gene facilitated SMAD2/3 binding to the BAMBI promoter via increasing BAMBI associated H3K4me1 and H3K27ac modification. Enforced expression of BAMBI in NPC cells suppressed cell proliferation and invasiveness. Our data suggested that FOXA1 is a master factor in controlling the TGF-β-stimulated transcriptome and a regulator of TGF-β biological functions in NPC oncogenesis.
鼻咽癌（NPC）是一种独特的头颈部鳞状细胞癌亚型，以其高转移潜能而臭名昭著。在本研究中，我们报道了 FOXA1 蛋白在 NPC 细胞中减少。FOXA1 的缺失与淋巴结转移和预后不良有关。沉默 NP69 和 C666-1 NPC 细胞中的 FOXA1 加速了细胞增殖和迁移，而 FOXA1 的重新表达则产生相反的效果。微阵列和 RNA-seq 分析显示，FOXA1 在 NPC 细胞中的重新表达重新编程了 TGF-β 刺激的转录程序，其特征是促进 TGF-β诱导的肿瘤抑制靶基因，但抑制 NPC 细胞中 TGF-β诱导的癌基因表达，导致 NPC 细胞对 TGF-β的生长抑制作用的敏感性恢复。BAMBI 是一种 TGF-β 反应性肿瘤抑制因子，在 NPC 细胞中被 FOXA1 诱导。FOXA1 在 BAMBI 基因上的结合通过增加 BAMBI 相关的 H3K4me1 和 H3K27ac 修饰，促进 SMAD2/3 结合到 BAMBI 启动子上。在 NPC 细胞中强制表达 BAMBI 抑制了细胞增殖和侵袭性。我们的数据表明，FOXA1 是控制 TGF-β 刺激的转录组的主要因素，也是 TGF-β 在 NPC 致癌作用中生物学功能的调节剂。
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