Acid sphingomyelinase determines melanoma progression and metastatic behaviour via the microphtalmia-associated transcription factor signalling pathway
Acid sphingomyelinase determines melanoma progression and metastatic behaviour via the microphtalmia-associated transcription factor signalling pathway
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DOI：
10.1038/cdd.2013.173
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发表时间：
2014-04-01
影响因子：
12.4
通讯作者：
Perrotta, C.
中科院分区：
文献类型：
--
作者：
Bizzozero, L.;Cazzato, D.;Perrotta, C.
黑色素瘤是一种快速生长和高度转移的癌症，死亡率高，缺乏解决方案。因此，新的治疗策略和肿瘤阶段的生物标志物的鉴定特别相关。我们在这里报告了一种新的生物标志物和可能的候选治疗靶点，鞘脂代谢酶酸性鞘磷脂酶（A-SMase）。人黑色素瘤活检组织中A-SMase表达与肿瘤分期呈负相关.在黑色素瘤的小鼠模型中以及在衍生自小鼠和人黑色素瘤的细胞系上的研究表明，A-SMase表达水平实际上决定了黑色素瘤细胞在色素沉着、肿瘤进展、侵袭性和转移能力方面的恶性表型。A-SMase的作用由细胞外信号调节激酶的活化、随后的微眼症相关转录因子（Mitf）的蛋白酶体降解以及细胞周期蛋白依赖性激酶2、Bcl-2和c-Met（Mitf的下游靶点，参与肿瘤细胞增殖、存活和转移）的抑制介导。
Melanoma is a rapidly growing and highly metastatic cancer with high mortality rates, for which a resolutive treatment is lacking. Identification of novel therapeutic strategies and biomarkers of tumour stage is thus of particular relevance. We report here on a novel biomarker and possible candidate therapeutic target, the sphingolipid metabolising enzyme acid sphingomyelinase (A- SMase). A- SMase expression correlates inversely with tumour stage in human melanoma biopsies. Studies in a mouse model of melanoma and on cell lines derived from mouse and human melanomas demonstrated that A- SMase levels of expression actually determine the malignant phenotype of melanoma cells in terms of pigmentation, tumour progression, invasiveness and metastatic ability. The action of A- SMase is mediated by the activation of the extracellular signal-regulated kinase, the subsequent proteasomal degradation of the Microphtalmia-associated transcription factor (Mitf) and inhibition of cyclin-dependent kinase 2, Bcl-2 and c-Met, downstream targets of Mitf involved in tumour cell proliferation, survival and metastatisation.