Adenylosuccinate lyase enhances aggressiveness of endometrial cancer by increasing killer cell lectin-like receptor C3 expression by fumarate
Adenylosuccinate lyase enhances aggressiveness of endometrial cancer by increasing killer cell lectin-like receptor C3 expression by fumarate
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DOI：
10.1038/s41374-017-0017-0
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发表时间：
2018-04-01
影响因子：
5
通讯作者：
Morii, Eiichi
中科院分区：
文献类型：
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作者：
Park, Haengki;Ohshima, Kenji;Morii, Eiichi
腺苷琥珀酸裂解酶(ADSL)是一种在从头合成嘌呤过程中起重要作用的酶。虽然ADSL在多种恶性肿瘤中表达上调，如结直肠癌、乳腺癌、前列腺癌以及神经胶质瘤，但ADSL表达上调导致癌症的机制尚不清楚。我们之前进行了鸟枪式蛋白质组学分析，以表征与乙醛脱氢酶(ALDH)高细胞群的特性相关的特定蛋白质，据报道，这种高细胞群参与了肿瘤的发生，并表明ADSL在ALDH高细胞群的子宫内膜癌中表达上调。在这里，我们发现ADSL通过调节杀伤细胞凝集素样受体C3(KLRC3)的表达参与子宫内膜癌的侵袭性，KLRC3是自然杀伤细胞上表达的受体。免疫组织化学分析显示，随着子宫内膜样癌组织分化程度的降低和原发肿瘤进展程度的增加，ADSL的表达也随之增加。ADSL在子宫内膜癌细胞中的敲除降低了细胞的增殖、迁移和侵袭能力，并使细胞呈现出更圆的形状。DNA芯片分析和实时定量聚合酶链式反应显示，KLRC3在ADSL基因敲除细胞中的表达降低。子宫内膜癌细胞中KLRC3基因的敲除导致与ADSL基因敲除相同的表型。此外，ADSL可以产生的富马酸在ADSL基因敲除细胞中恢复了KLRC3的表达，这表明ADSL产生的富马酸可以调节KLRC3的表达。我们的研究结果表明，ADSL通过富马酸调节KLRC3的表达来增强细胞的增殖、迁移和侵袭能力。
Adenylosuccinate lyase (ADSL) is an enzyme that plays important roles in de novo purine synthesis. Although ADSL was reported to be upregulated in various malignancies, such as colorectal, breast, and prostate cancer, as well as gliomas, the mechanism by which elevated ADSL expression contributes to cancer has not been elucidated. We previously performed a shotgun proteomics analysis to characterize specific proteins associated with the properties of the aldehyde dehydrogenase (ALDH)-high cell population, which was reported to be involved in tumorigenic potential, and showed that ADSL expression is upregulated in the ALDH-high population of endometrial cancer. Here, we showed that ADSL is involved in endometrial cancer aggressiveness by regulating expression of killer cell lectin-like receptor C3 (KLRC3), which is a receptor expressed on natural killer cells. Immunohistochemical analysis indicated that ADSL expression increased as endometrioid carcinoma specimens became more poorly differentiated and higher degree of primary tumor progression. Knockdown of ADSL in endometrial cancer cells decreased cell proliferation, migration, and invasive capability, and caused the cells to adopt a more rounded shape. DNA microarray analysis and quantitative real-time PCR showed that KLRC3 expression was decreased in ADSL knockdown cells. Knockdown of KLRC3 in endometrial cancer cells resulted in the same phenotype as knockdown of ADSL. Moreover, fumarate, which could be produced by ADSL and was recently shown to be an oncometabolite, recovered KLRC3 expression in ADSL knockdown cells, suggesting that fumarate produced by ADSL could regulate KLRC3 expression. Our findings indicate that ADSL enhances cell proliferation, migration, and invasive capability through regulation of KLRC3 expression by fumarate.