MAPKAPK2 (MK2) 抑制介导头颈部鳞状细胞癌中辐射诱导的炎性细胞因子产生和肿瘤生长。,Oncogene

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MAPKAPK2 (MK2) 抑制介导头颈部鳞状细胞癌中辐射诱导的炎性细胞因子产生和肿瘤生长。
Oncogene ( IF 6.9 ) Pub Date : 2019-08-15 , DOI: 10.1038/s41388-019-0945-9
Kiersten L Berggren _{1,

2} , Sebastian Restrepo Cruz _{1,

2} , Michael D Hixon _{1,

2} , Andrew T Cowan _{3,

4} , Stephen B Keysar ₅ , Stephanie Craig ₆ , Jacqueline James ₆ , Marc Barry ₇ , Michelle A Ozbun _{4,

8} , Antonio Jimeno ₅ , Dennis J McCance ₇ , Ellen J Beswick ₉ , Gregory N Gan ₁₀

Affiliation

Department of Internal Medicine, Section of Radiation Oncology, The University of New Mexico, Albuquerque, NM, USA.
The University of New Mexico Comprehensive Cancer Center, Cancer Therapeutics Program, Albuquerque, NM, USA.
Department of Surgery, Division of Otolaryngology, The University of New Mexico, Albuquerque, NM, USA.
The University of New Mexico Comprehensive Cancer Center, Cancer Biology and Signaling Program, Albuquerque, NM, USA.
Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
Center for Cancer Research and Cell Biology, Queen's University, Belfast, BT9 7BL, Northern Ireland.
Department of Pathology, The University of New Mexico, Albuquerque, NM, USA.
Department of Molecular Genetics and Microbiology, The University of New Mexico, Albuquerque, NM, USA.
Department of Internal Medicine, Division of Gastroenterology, Hepataology, and Nutrition, University of Utah, Salt Lake City, UT, USA.
Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS, USA.

放射治疗 (RT) 是治疗头颈部鳞状细胞癌 (HNSCC) 的基石，但治疗失败和疾病复发很常见。p38/MK2 通路响应细胞应激源（包括辐射）而被激活，并促进多种癌症的肿瘤炎症。我们研究了 HNSCC 中的 MK2 通路激活以及 MK2 和 RT 在体外和体内的相互作用。我们使用口咽 SCC 组织微阵列、HNSCC 细胞系和患者来源的异种移植 (PDX) 肿瘤模型的组合来研究 RT 对 MK2 通路激活的影响，并确定药理学 (PF-3644022) 和遗传 (siRNA) 方法影响肿瘤生长。我们表明，高磷酸化 MK2 (p-MK2) 水平与 p16 阴性 HNSCC 患者的疾病特异性存活率恶化有关。RT 增加 p16 阳性、HPV 阳性和 p16 阴性、HPV 阴性 HNSCC 细胞系中的 p-MK2。MK2 的体外药理学抑制或基因沉默消除了 RT 诱导的 p-MK2 增加；炎性细胞因子表达和下游 MK2 靶标热休克蛋白 27 (HSP27) 的表达；和上皮-间充质转化的标志物。用 RT 和 MK2 抑制剂联合治疗的小鼠 PDX 模型经历了肿瘤生长减少和存活增加。我们的结果表明 MK2 是头颈癌的潜在预后生物标志物，并且 MK2 通路激活可以介导 HNSCC 中的辐射抗性。HPV 阳性和 p16 阴性、HPV 阴性的 HNSCC 细胞系。MK2 的体外药理学抑制或基因沉默消除了 RT 诱导的 p-MK2 增加；炎性细胞因子表达和下游 MK2 靶标热休克蛋白 27 (HSP27) 的表达；和上皮-间充质转化的标志物。用 RT 和 MK2 抑制剂联合治疗的小鼠 PDX 模型经历了肿瘤生长减少和存活增加。我们的结果表明 MK2 是头颈癌的潜在预后生物标志物，并且 MK2 通路激活可以介导 HNSCC 中的辐射抗性。HPV 阳性和 p16 阴性、HPV 阴性的 HNSCC 细胞系。MK2 的体外药理学抑制或基因沉默消除了 RT 诱导的 p-MK2 增加；炎性细胞因子表达和下游 MK2 靶标热休克蛋白 27 (HSP27) 的表达；和上皮-间充质转化的标志物。用 RT 和 MK2 抑制剂联合治疗的小鼠 PDX 模型经历了肿瘤生长减少和存活增加。我们的结果表明 MK2 是头颈癌的潜在预后生物标志物，并且 MK2 通路激活可以介导 HNSCC 中的辐射抗性。热休克蛋白 27 (HSP27)；和上皮-间充质转化的标志物。用 RT 和 MK2 抑制剂联合治疗的小鼠 PDX 模型经历了肿瘤生长减少和存活增加。我们的结果表明 MK2 是头颈癌的潜在预后生物标志物，并且 MK2 通路激活可以介导 HNSCC 中的辐射抗性。热休克蛋白 27 (HSP27)；和上皮-间充质转化的标志物。用 RT 和 MK2 抑制剂联合治疗的小鼠 PDX 模型经历了肿瘤生长减少和存活增加。我们的结果表明 MK2 是头颈癌的潜在预后生物标志物，并且 MK2 通路激活可以介导 HNSCC 中的辐射抗性。

"点击查看英文标题和摘要"

MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma.

Radiation therapy (RT) is a cornerstone of treatment in the management of head and neck squamous cell carcinomas (HNSCC), yet treatment failure and disease recurrence are common. The p38/MK2 pathway is activated in response to cellular stressors, including radiation, and promotes tumor inflammation in a variety of cancers. We investigated MK2 pathway activation in HNSCC and the interaction of MK2 and RT in vitro and in vivo. We used a combination of an oropharyngeal SCC tissue microarray, HNSCC cell lines, and patient-derived xenograft (PDX) tumor models to study the effect of RT on MK2 pathway activation and to determine how inhibition of MK2 by pharmacologic (PF-3644022) and genetic (siRNA) methods impacts tumor growth. We show that high phosphorylated MK2 (p-MK2) levels are associated with worsened disease-specific survival in p16-negative HNSCC patients. RT increased p-MK2 in both p16-positive, HPV-positive and p16-negative, HPV-negative HNSCC cell lines. Pharmacologic inhibition or gene silencing of MK2 in vitro abrogated RT-induced increases in p-MK2; inflammatory cytokine expression and expression of the downstream MK2 target, heat shock protein 27 (HSP27); and markers of epithelial-to-mesenchymal transition. Mouse PDX models treated with a combination of RT and MK2 inhibitor experienced decreased tumor growth and increased survival. Our results suggest that MK2 is a potential prognostic biomarker for head and neck cancer and that MK2 pathway activation can mediate radiation resistance in HNSCC.

更新日期：2019-08-16

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