Involvement of c-Fos in the Promotion of Cancer Stem-like Cell Properties in Head and Neck Squamous Cell Carcinoma.
Involvement of c-Fos in the Promotion of Cancer Stem-like Cell Properties in Head and Neck Squamous Cell Carcinoma.
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DOI：
10.1158/1078-0432.ccr-16-2811
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发表时间：
2017-06-15
期刊：
影响因子：
--
通讯作者：
Ray RB
中科院分区：
文献类型：
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作者：
Muhammad N;Bhattacharya S;Steele R;Phillips N;Ray RB
头颈鳞状细胞癌（HNSCC）是全球第六大常见癌症。尽管手术技术、化疗和放疗以及支持治疗的改进改善了 HNSCC 患者的生活质量，但区域和远处复发仍然很常见。最近的证据表明，癌症干细胞样细胞（CSC）在复发和化疗耐药中发挥着重要作用。我们之前观察到 c-Fos 在 HNSCC 球体形成细胞中高度上调。 c-Fos 上调对 HNSCC-CSC 生物学的影响尚不清楚。在这项研究中，我们研究了 c-Fos 在 HNSCC 干性更新和肿瘤生长中的作用。我们生成了异位表达 c-Fos 基因的稳定 HNSCC 细胞系。在非致瘤性 MDA1386Tu 细胞中外源表达 c-Fos 使这些细胞在裸鼠中产生致瘤性。此外，与亲代细胞相比，将过表达 c-Fos 的 Cal27 细胞（致瘤性）皮下移植到免疫功能低下的小鼠体内可增强肿瘤生长。机制研究表明，c-Fos 过表达增强了上皮间质转化 (EMT) 状态和 CSC 标记物（Nanog、c-Myc、Sox2 和 Notch1）的表达。 HNSCC 细胞中 c-Fos 的异位表达也显示球体形成数量增加。我们进一步观察到 c-Fos 的过度表达增加了 HNSCC 细胞中 pERK 和细胞周期蛋白 D1 的表达。总之，我们的结果强烈表明 c-Fos 作为 HNSCC 细胞中 EMT 和癌症干细胞重编程调节剂的新作用，这可能具有作为 CSC 导向的治疗方法来改善 HNSCC 治疗的潜力。
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Although improvements in surgical techniques, chemotherapy and radiation delivery, and supportive care have improved quality of life for patients with HNSCC, regional and distant recurrence remain common. Recent evidence suggests that cancer stem-like cells (CSCs) play a significant role in recurrence and chemo-resistant. We previously observed that c-Fos was highly up-regulated in the HNSCC sphere forming cells. Consequences of c-Fos upregulation for the biology of HNSCC-CSCs are poorly understood. In this study, we investigated the role of c-Fos in renewal of stemness of HNSCC and tumor growth. We generated stable HNSCC cell lines ectopically expressing the c-Fos gene. Exogenous expression of c-Fos in non-tumorigenic MDA1386Tu cells makes these cells tumorigenic in nude mice. Further, subcutaneous transplantation of c-Fos overexpressing Cal27 cells (tumorigenic) into immunocompromised mice enhanced tumor growth as compared to parental cells. Mechanistic investigations demonstrated that c-Fos overexpression enhanced the epithelial mesenchymal transition (EMT) state and expression of CSC markers (Nanog, c-Myc, Sox2 and Notch1). Ectopic expression of c-Fos in HNSCC cells also display increased number of sphere formation. We further observed that overexpression of c-Fos increased the expression of pERK and cyclin D1 in HNSCC cells. Together, our results strongly suggest a novel role of c-Fos as a regulator of EMT and cancer stem cell reprogramming in HNSCC cells, which may hold potential as a CSC-directed therapeutic approach to improve HNSCC treatment.