BACKGROUND Tumor cells display metabolic changes that correlate with malignancy, including an elevated hydrolysis of monoacylglycerol (MAG) in various cancer types. However, evidence is absent for the relationship between MAG lipolysis and NSCLC. METHODS MAG hydrolase activity assay, migration, invasion, proliferation, lipids quantification, and transactivation assays were performed in vitro. Tumor xenograft studies and lung metastasis assays were examined in vivo. The correlations of MAGL/ABHD6 expression in cancerous tissues with the clinicopathological characteristics and survival of NSCLC patients were validated. FINDINGS ABHD6 functions as the primary MAG lipase and an oncogene in NSCLC. MAG hydrolase activities were more than 11-fold higher in cancerous lung tissues than in paired non-cancerous tissues derived from NSCLC patients. ABHD6, instead of MAGL, was significantly associated with advanced tumor node metastasis (TNM) stage (HR, 1.382; P = 0.004) and had a negative impact on the overall survival of NSCLC patients (P = 0.001). ABHD6 silencing reduced migration and invasion of NSCLC cells in vitro as well as metastatic seeding and tumor growth in vivo. Conversely, ectopic overexpression of ABHD6 provoked the pathogenic potential. ABHD6 blockade significantly induced intracellular MAG accumulation which activated PPARα/γ signaling and inhibited cancer pathophysiology. INTERPRETATION The present study provide evidence for a previously uncovered pro-oncogenic function of ABHD6 in NSCLC, with the outlined metabolic mechanisms shedding light on new potential strategies for anticancer therapy. FUND: This work was supported by the Project for Major New Drug Innovation and Development (2015ZX09501010 and 2018ZX09711001-002-003).

中文翻译：

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ABHD6增强的单酰基甘油脂解促进了NSCLC发病机理。

背景技术肿瘤细胞显示出与恶性肿瘤相关的代谢变化，包括在各种癌症类型中单酰基甘油（MAG）的水解增加。但是，尚无关于MAG脂解与NSCLC之间关系的证据。方法在体外进行MAG水解酶活性测定，迁移，侵袭，增殖，脂质定量和反式激活测定。在体内检查了肿瘤异种移植研究和肺转移测定。验证了癌组织中MAGL / ABHD6表达与NSCLC患者的临床病理特征和生存的相关性。结论ABHD6在NSCLC中起主要的MAG脂肪酶和癌基因的作用。在癌性肺组织中，MAG水解酶活性比非小细胞肺癌患者的成对非癌性组织高11倍以上。ABHD6，而不是MAGL，与晚期肿瘤淋巴结转移（TNM）阶段显着相关（HR，1.382; P = 0.004），并且对NSCLC患者的总体生存有负面影响（P = 0.001）。ABHD6沉默可减少NSCLC细胞在体外的迁移和侵袭，以及体内转移性播种和肿瘤生长。相反，ABHD6的异位表达激发了致病潜力。ABHD6阻断可显着诱导细胞内MAG积聚，从而激活PPARα/γ信号传导并抑制癌症病理生理。解释本研究为ABHD6在NSCLC中以前未发现的促癌作用提供了证据，其概述的代谢机制为抗癌治疗的新潜在策略提供了线索。基金：