Purpose

Oropharynx squamous cell carcinoma (OPSCC) is a subtype of head and neck squamous cell carcinoma (HNSCC) arising from the base of the tongue, lingual tonsils, tonsils, oropharynx or pharynx. The majority of HPV-positive OPSCCs has a good prognosis, but a fraction of them has a poor prognosis, similar to HPV-negative OPSCCs. An in-depth understanding of the molecular mechanisms underlying OPSCC is mandatory for the identification of novel prognostic biomarkers and/or novel therapeutic targets.

Methods

14 HPV-positive and 15 HPV-negative OPSCCs with 5-year follow-up information were subjected to gene expression profiling and, subsequently, compared to three extensive published OPSCC cohorts to define robust biomarkers for HPV-negative lesions. Validation of Aldo-keto-reductases 1C3 (AKR1C3) by qRT-PCR was carried out on an independent cohort (n = 111) of OPSCC cases. In addition, OPSCC cell lines Fadu and Cal-27 were treated with Cisplatin and/or specific AKR1C3 inhibitors to assess their (combined) therapeutic effects.

Results

Gene set enrichment analysis (GSEA) on the four datasets revealed that the genes down-regulated in HPV-negative samples were mainly involved in immune system, whereas those up-regulated mainly in glutathione derivative biosynthetic and xenobiotic metabolic processes. A panel of 30 robust HPV-associated transcripts was identified, with AKR1C3 as top-overexpressed transcript in HPV-negative samples. AKR1C3 expression in 111 independent OPSCC cases positively correlated with a worse survival, both in the entire cohort and in HPV-positive samples. Pretreatment with a selective AKR1C3 inhibitor potentiated the effect of Cisplatin in OPSCC cells exhibiting higher basal AKR1C3 expression levels.

Conclusions

We identified AKR1C3 as a potential prognostic biomarker in OPSCC and as a potential drug target whose inhibition can potentiate the effect of Cisplatin.

中文翻译：

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AKR1C3 是口咽肿瘤的生物标志物和药物靶点

目的

口咽鳞状细胞癌 (OPSCC) 是头颈部鳞状细胞癌 (HNSCC) 的一种亚型，起源于舌根、舌扁桃体、扁桃体、口咽或咽部。大多数 HPV 阳性 OPSCC 预后良好，但其中一小部分预后较差，类似于 HPV 阴性 OPSCC。深入了解 OPSCC 的分子机制对于识别新的预后生物标志物和/或新的治疗靶标是必不可少的。

方法

对具有 5 年随访信息的 14 名 HPV 阳性和 15 名 HPV 阴性 OPSCC 进行基因表达谱分析，随后与三个广泛发表的 OPSCC 队列进行比较，以确定 HPV 阴性病变的可靠生物标志物。通过 qRT-PCR 对醛酮还原酶 1C3 (AKR1C3) 的验证在 OPSCC 病例的独立队列 ( n = 111) 中进行。此外，OPSCC 细胞系 Fadu 和 Cal-27 用顺铂和/或特定的 AKR1C3 抑制剂处理，以评估它们的（组合）治疗效果。

结果

对四个数据集的基因集富集分析 (GSEA) 显示，HPV 阴性样本中下调的基因主要参与免疫系统，而上调的基因主要参与谷胱甘肽衍生物的生物合成和异生物质代谢过程。确定了一组 30 个强大的 HPV 相关转录物，其中 AKR1C3 作为 HPV 阴性样品中过度表达的转录物。AKR1C3 在 111 个独立的 OPSCC 病例中的表达与较差的生存率呈正相关，无论是在整个队列中还是在 HPV 阳性样本中。用选择性 AKR1C3 抑制剂预处理可增强顺铂在 OPSCC 细胞中的作用，这些细胞表现出更高的基础 AKR1C3 表达水平。

结论

我们将 AKR1C3 确定为 OPSCC 中潜在的预后生物标志物，并作为潜在的药物靶点，其抑制作用可以增强顺铂的作用。