Regulation of submaxillary gland androgen-regulated protein 3A via estrogen receptor 2 in radioresistant head and neck squamous cell carcinoma cells.
Regulation of submaxillary gland androgen-regulated protein 3A via estrogen receptor 2 in radioresistant head and neck squamous cell carcinoma cells.
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DOI：
10.1186/s13046-017-0496-2
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发表时间：
2017-02-06
期刊：
影响因子：
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通讯作者：
Hess J
中科院分区：
文献类型：
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作者：
Grünow J;Rong C;Hischmann J;Zaoui K;Flechtenmacher C;Weber KJ;Plinkert P;Hess J
内在或获得性放射抗性的分子机制是头颈鳞状细胞癌（HNSCC）治疗的关键障碍，并且仍然是无进展和疾病特异性生存的主要障碍。 HNSCC 细胞系单独采用分次照射（IR，4×2Gy）方案或与雌激素受体信号拮抗剂联合处理，并通过集落形成测定（CFA）测定活力。通过 RQ-PCR、蛋白质印迹分析和免疫荧光染色，以及对含有接受根治性或辅助放疗的口咽鳞状细胞癌 (OPSCC) 患者肿瘤切片的组织微阵列进行免疫组织化学染色，在体外评估肿瘤细胞中颌下腺雄激素调节蛋白 3A (SMR3A) 和雌激素受体 2 (ESR2) 的表达。具有不同 SMR3A 和 ESR2 表达模式的亚组与临床参数和生存结果（包括多变量分析）相关。分段照射 (IR) 显示肿瘤细胞积聚，SMR3A 表达显着，同时雌激素受体 2 (ESR2) 上调。 SMR3A 的 ESR2 依赖性调节得到雌二醇 (E2) 刺激后诱导表达的支持，而雌二醇 (E2) 刺激后的诱导表达则分别因与 4-羟基他莫昔芬 (TAM) 或氟维司群联合治疗而受损。根据 CFA 测定，两种药物均显着使 FaDu 细胞对分级 IR 敏感，并加速细胞凋亡。这些数据表明 ESR2 在放射抗性中发挥着关键作用，并且 SMR3A 可能作为活性 ESR2 信号传导的替代标记。与这一假设相符，与 SMR3A 低表达的肿瘤相比，SMR3A 高表达的 ESR2 阳性口咽鳞状细胞癌 (OPSCC) 具有不利的无进展生存和疾病特异性生存。总之，我们的研究结果提供了令人信服的实验证据，表明具有 SMR3A 和 ESR2 共表达的 HNSCC 治疗失败的风险较高，这些患者可能会受益于临床上成熟的针对雌激素受体信号传导的药物。本文的在线版本 (doi:10.1186/s13046-017-0496-2) 包含补充材料，可供授权用户使用。
Molecular mechanisms of intrinsic or acquired radioresistance serve as critical barrier for curative therapy of head and neck squamous cell carcinoma (HNSCC) and remain a major obstacle for progression-free and disease-specific survival. HNSCC cell lines were treated with a protocol of fractionated irradiation (IR, 4× 2Gy) alone or in combination with antagonists of estrogen receptor signaling and viability was determined by a colony-forming assay (CFA). Expression of submaxillary gland androgen-regulated protein 3A (SMR3A) and estrogen receptor 2 (ESR2) were assessed in tumor cells in vitro by RQ-PCR, Western blot analysis and immunofluorescence staining, and by immunohistochemical staining of tissue microarrays containing tumor sections from patients with oropharyngeal squamous cell carcinoma (OPSCC), which were treated by definitive or adjuvant radiotherapy. Subgroups with distinct SMR3A and ESR2 expression patterns were correlated with clinical parameters and survival outcome including multivariable analysis. Fractionated irradiation (IR) revealed an accumulation of tumor cells with prominent SMR3A expression, which was accompanied by an up-regulation of the estrogen receptor 2 (ESR2). ESR2-dependent regulation of SMR3A was supported by induced expression after stimulation with estradiol (E2), which was impaired by co-treatment with 4-Hydroxytamoxifen (TAM) or Fulvestrant, respectively. Both drugs significantly sensitized FaDu cells to fractionated IR as determined by a CFA and accelerated apoptosis. These data suggest a critical role of ESR2 in radioresistance and that SMR3A might serve as a surrogate marker for active ESR2 signaling. In line with this assumption, ESR2-positive oropharyngeal squamous cell carcinoma (OPSCC) with high SMR3A expression had an unfavorable progression-free and disease-specific survival as compared to those tumors with low SMR3A expression. In summary, our findings provide compelling experimental evidence that HNSCC with SMR3A and ESR2 co-expression have a higher risk for treatment failure and these patients might benefit from clinically well-established drugs targeting estrogen receptor signaling. The online version of this article (doi:10.1186/s13046-017-0496-2) contains supplementary material, which is available to authorized users.