Lung cancer causes more deaths than any other cancer. Sphingolipids encompass metabolically interconnected species whose balance has pivotal effects on proliferation, migration, and apoptosis. In this study, we paralleled quantification of sphingolipid species with quantitative (q)PCR analyses of metabolic enzymes in order to identify dysregulated routes of sphingolipid metabolism in different subtypes of lung cancers. Lung samples were submitted to histopathological reexamination in order to confirm cancer type/subtype, which included adenocarcinoma histological subtypes and squamous cell and neuroendocrine carcinomas. Compared with benign lesions and tumor-free parenchyma, all cancers featured decreased sphingosine-1-phosphate and SMs. qPCR analyses evidenced differential mechanisms leading to these alterations between cancer types, with neuroendocrine carcinomas upregulating SGPL1, but CERT1 being downregulated in adenocarcinomas and squamous cell carcinomas. 2-Hydroxyhexosylceramides (2-hydroxyHexCers) were specifically increased in adenocarcinomas. While UDP-glycosyltransferase 8 (UGT8) transcript levels were increased in all cancer subtypes, fatty acid 2-hydroxylase (FA2H) levels were higher in adenocarcinomas than in squamous and neuroendocrine carcinomas. As a whole, we report differing mechanisms through which all forms of lung cancer achieve low SM and lysosphingolipids. Our results also demonstrate that FA2H upregulation is required for the accumulation of 2-hydroxyHexCers in lung cancers featuring high levels of UGT8.

中文翻译：

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高FA2H和UGT8成绩单水平预测在肺腺癌中羟基化的己糖基神经酰胺蓄积。

肺癌比其他癌症导致更多的死亡。鞘脂包括代谢互连的物种，其平衡对增殖，迁移和凋亡具有关键作用。在这项研究中，我们将鞘脂种类的定量与代谢酶的定量（q）PCR分析并行进行，以鉴定不同亚型肺癌中鞘脂代谢的失调途径。肺样品接受组织病理学复查，以确认癌症类型/亚型，其中包括腺癌组织学亚型，鳞状细胞癌和神经内分泌癌。与良性病变和无肿瘤的实质相比，所有癌症的特征都是鞘氨醇-1-磷酸和SM减少。qPCR分析了导致这些癌症类型之间发生这些改变的不同机制，SGPL1，但CERT1在腺癌和鳞状细胞癌中被下调。2-羟基己糖基神经酰胺（2-hydroxyHexCers）在腺癌中特异性升高。尽管在所有癌症亚型中UDP-糖基转移酶8（UGT8）的转录水平均升高，但腺癌中的脂肪酸2-羟化酶（FA2H）水平高于鳞状和神经内分泌癌。总体而言，我们报告了各种形式的肺癌实现低SM和糖鞘脂的不同机制。我们的研究结果还表明，FA2H上调是特征性UGT8高水平肺癌中2-hydroxyHexCers积累所必需的。