Division of Molecular Carcinogenesis, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Molecular Oncology, Fujita Health University, Toyoake, Japan.
J Cell Mol Med. 2020 Oct;24(20):11949-11959. doi: 10.1111/jcmm.15817. Epub 2020 Sep 9.
Sphingolipids constitute a class of bio-reactive molecules that transmit signals and exhibit a variety of physical properties in various cell types, though their functions in cancer pathogenesis have yet to be elucidated. Analyses of gene expression profiles of clinical specimens and a panel of cell lines revealed that the ceramide synthase gene CERS6 was overexpressed in non-small-cell lung cancer (NSCLC) tissues, while elevated expression was shown to be associated with poor prognosis and lymph node metastasis. NSCLC profile and in vitro luciferase analysis results suggested that CERS6 overexpression is promoted, at least in part, by reduced miR-101 expression. Under a reduced CERS6 expression condition, the ceramide profile became altered, which was determined to be associated with decreased cell migration and invasion activities in vitro. Furthermore, CERS6 knockdown suppressed RAC1-positive lamellipodia/ruffling formation and attenuated lung metastasis efficiency in mice, while forced expression of CERS6 resulted in an opposite phenotype in examined cell lines. Based on these findings, we consider that ceramide synthesis by CERS6 has important roles in lung cancer migration and metastasis.
鞘脂类构成了一类生物活性分子，它们在各种细胞类型中传递信号并表现出多种物理性质，但其在癌症发病机制中的功能尚未阐明。对临床标本和一系列细胞系的基因表达谱分析表明，在非小细胞肺癌（NSCLC）组织中，神经酰胺合酶基因 CERS6 过表达，而高表达与预后不良和淋巴结转移相关。NSCLC 谱和体外荧光素酶分析结果表明，CERS6 过表达至少部分是由 miR-101 表达降低所促进的。在 CERS6 表达降低的情况下，神经酰胺谱发生改变，这与体外细胞迁移和侵袭活性降低有关。此外，CERS6 敲低抑制 RAC1 阳性的片状伪足/皱襞形成，并降低小鼠肺转移效率，而 CERS6 的强制表达导致在被检查的细胞系中出现相反的表型。基于这些发现，我们认为 CERS6 的神经酰胺合成在肺癌迁移和转移中具有重要作用。
