Purpose: Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) is associated with daily marijuana use and is also increasing in parallel with increased marijuana use in the United States. Our study is designed to define the interaction between cannabinoids and HPV-positive HNSCC. Experimental Design: The expression of cannabinoid receptors CNR1 and CNR2 was analyzed using The Cancer Genome Atlas (TCGA) HNSCC data. We used agonists, antagonists, siRNAs, or shRNA-based models to explore the roles of CNR1 and CNR2 in HPV-positive HNSCC cell lines and animal models. Cannabinoid downstream pathways involved were determined by Western blotting and analyzed in a primary HPV HNSCC cohort with single-sample gene set enrichment analysis (ssGSEA) and the OncoGenome Positioning System (Onco-GPS). Results: In TCGA cohort, the expression of CNR1 and CNR2 was elevated in HPV-positive HNSCC compared with HPV-negative HNSCC, and knockdown of CNR1 / CNR2 expression inhibited proliferation in HPV-positive HNSCC cell lines. Specific CNR1 and CNR2 activation as well as nonselective cannabinoid receptor activation in cell lines and animal models promoted cell growth, migration, and inhibited apoptosis through p38 MAPK pathway activation. CNR1/CNR2 antagonists suppressed cell proliferation and migration and induced apoptosis. Using whole-genome expression analysis in a primary HPV HNSCC cohort, we identified specific p38 MAPK pathway activation signature in tumors from HPV HNSCC patients with objective measurement of concurrent cannabinoid exposure. Conclusions: Cannabinoids can promote progression of HPV-positive HNSCC through p38 MAPK pathway activation.

中文翻译：

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大麻素通过 p38 MAPK 激活促进 HPV 阳性头颈部鳞状细胞癌的进展。

目的：与人乳头瘤病毒 (HPV) 相关的头颈部鳞状细胞癌 (HNSCC) 与日常大麻使用有关，并且随着美国大麻使用的增加而增加。我们的研究旨在确定大麻素与 HPV 阳性 HNSCC 之间的相互作用。实验设计：使用癌症基因组图谱 (TCGA) HNSCC 数据分析大麻素受体 CNR1 和 CNR2 的表达。我们使用激动剂、拮抗剂、siRNA 或基于 shRNA 的模型来探索 CNR1 和 CNR2 在 HPV 阳性 HNSCC 细胞系和动物模型中的作用。涉及的大麻素下游途径通过蛋白质印迹确定，并在初级 HPV HNSCC 队列中使用单样本基因集富集分析 (ssGSEA) 和 OncoGenome 定位系统 (Onco-GPS) 进行分析。结果：在 TCGA 队列中，与HPV阴性HNSCC相比，HPV阳性HNSCC中CNR1和CNR2的表达升高，并且CNR1/CNR2表达的敲低抑制了HPV阳性HNSCC细胞系的增殖。细胞系和动物模型中的特定 CNR1 和 CNR2 激活以及非选择性大麻素受体激活通过 p38 MAPK 通路激活促进细胞生长、迁移和抑制细胞凋亡。CNR1/CNR2 拮抗剂抑制细胞增殖和迁移并诱导细胞凋亡。在主要 HPV HNSCC 队列中使用全基因组表达分析，我们确定了 HPV HNSCC 患者肿瘤中特定的 p38 MAPK 通路激活特征，并客观测量了并发大麻素暴露。结论：大麻素可通过激活 p38 MAPK 通路促进 HPV 阳性 HNSCC 的进展。