Department of Head and Neck Surgery, Houston, TX, USA.
Oncogene. 2011 Jul 14;30(28):3163-73. doi: 10.1038/onc.2011.39. Epub 2011 Mar 7.
Although surgery and radiotherapy have been the standard treatment modalities for head and neck squamous cell carcinoma (HNSCC), the integration of cisplatin (CDDP)-based therapy has led to improvements in local and regional control of disease for patients. However, many trials show that only 10-20% of patients benefit from this treatment intensification, which can result in profound treatment-associated morbidity and mortality. Moreover, the marginal survival improvement suggests that CDDP resistance is an innate characteristic of HNSCC. To elucidate the biological mechanisms underpinning CDDP resistance in HNSCC, we utilized an experimental model of CDDP resistance in this disease. We first observed significant enhancements in local tumor growth and metastasis, as well as adverse survival, in CDDP-resistant (CR) tumors compared with sensitive tumors. To elucidate the molecular mechanisms of this phenotype, we undertook a systems biology-based approach utilizing high-throughput PCR arrays, and we identified a significant suppression of KiSS1 mRNA and protein expression in the CR cells, but no significant regions of genomic loss with array comparative genomic hybridization. Genetic suppression of KiSS1 in CDDP-sensitive cell lines rendered them CR, an observation that was mechanistically linked to alterations in glutathione S-transferase-π expression and function. We next confirmed that, in human HNSCC tumors, loss of KiSS1 expression was associated with metastatic human HNSCC tumors compared with non-metastatic tumors. Genetic reconstitution of KiSS1 in CR cells abrogated cellular migration and induced CDDP sensitivity. To confirm these findings in a murine model, either CR or KiSS1-transfected CR cells were studied in an orthotopic model of HNSCC, or survival studies revealed significant improvement in survival of the mice bearing CR-KiSS1 tumors. Mechanistically, alterations in apoptotic pathways and CDDP metabolism contributed to KiSS1-associated chemotherapy sensitization. These studies provided further direct evidence for the role of KiSS1 loss in biologically aggressive HNSCC and suggest potential targets for therapy in CR cancers.
虽然手术和放疗一直是头颈部鳞状细胞癌（HNSCC）的标准治疗方法，但顺铂（CDDP）为基础的治疗方法的整合导致了疾病局部和区域控制的改善。然而，许多试验表明，只有 10-20%的患者受益于这种治疗强化，这可能导致严重的治疗相关发病率和死亡率。此外，边缘生存的改善表明 CDDP 耐药是 HNSCC 的固有特征。为了阐明 HNSCC 中 CDDP 耐药的生物学机制，我们在该疾病中利用了 CDDP 耐药的实验模型。我们首先观察到与敏感肿瘤相比，CDDP 耐药（CR）肿瘤的局部肿瘤生长和转移以及不良生存显著增强。为了阐明这种表型的分子机制，我们采用了基于系统生物学的方法，利用高通量 PCR 阵列，我们发现 CR 细胞中 Kiss1 mRNA 和蛋白表达显著抑制，但阵列比较基因组杂交无明显基因组缺失区域。在 CDDP 敏感细胞系中遗传抑制 Kiss1 使它们成为 CR，这一观察结果与谷胱甘肽 S-转移酶-π表达和功能的改变有关。我们接下来证实，在人类 HNSCC 肿瘤中，Kiss1 表达缺失与转移性人类 HNSCC 肿瘤相关，而与非转移性肿瘤相比。在 CR 细胞中遗传重建 Kiss1 可消除细胞迁移并诱导 CDDP 敏感性。为了在鼠模型中证实这些发现，在 HNSCC 的原位模型中研究了 CR 或 Kiss1 转染的 CR 细胞，或生存研究显示，携带 CR-Kiss1 肿瘤的小鼠的生存显著改善。从机制上讲，凋亡途径和 CDDP 代谢的改变导致了 Kiss1 相关的化疗敏感性。这些研究为 Kiss1 缺失在生物学侵袭性 HNSCC 中的作用提供了进一步的直接证据，并提示 CR 癌症治疗的潜在靶点。
