Department of Molecular Oncology, School of Medicine, Fujita Health University, Toyoake, Japan.
Division of Molecular Carcinogenesis, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Cancer Sci. 2021 Jul;112(7):2770-2780. doi: 10.1111/cas.14928. Epub 2021 May 4.
Ceramide synthase 6 (CERS6) promotes lung cancer metastasis by stimulating cancer cell migration. To examine the underlying mechanisms, we performed luciferase analysis of the CERS6 promoter region and identified the Y-box as a cis-acting element. As a parallel analysis of database records for 149 non-small-cell lung cancer (NSCLC) cancer patients, we screened for trans-acting factors with an expression level showing a correlation with CERS6 expression. Among the candidates noted, silencing of either CCAAT enhancer-binding protein γ (CEBPγ) or Y-box binding protein 1 (YBX1) reduced the CERS6 expression level. Following knockdown, CEBPγ and YBX1 were found to be independently associated with reductions in ceramide-dependent lamellipodia formation as well as migration activity, while only CEBPγ may have induced CERS6 expression through specific binding to the Y-box. The mRNA expression levels of CERS6, CEBPγ, and YBX1 were positively correlated with adenocarcinoma invasiveness. YBX1 expression was observed in all 20 examined clinical lung cancer specimens, while 6 of those showed a staining pattern similar to that of CERS6. The present findings suggest promotion of lung cancer migration by possible involvement of the transcription factors CEBPγ and YBX1.
神经酰胺合酶 6（CERS6）通过刺激癌细胞迁移促进肺癌转移。为了研究潜在的机制，我们对 CERS6 启动子区域进行了荧光素酶分析，并确定了 Y 盒作为顺式作用元件。作为对 149 例非小细胞肺癌（NSCLC）癌症患者数据库记录的平行分析，我们筛选了与 CERS6 表达水平相关的反式作用因子。在注意到的候选物中，沉默 CCAAT 增强子结合蛋白γ（CEBPγ）或 Y 盒结合蛋白 1（YBX1）均可降低 CERS6 表达水平。敲低后，CEBPγ 和 YBX1 均与依赖神经酰胺的片状伪足形成以及迁移活性降低独立相关，而只有 CEBPγ 可能通过与 Y 盒的特异性结合诱导 CERS6 表达。CERS6、CEBPγ 和 YBX1 的 mRNA 表达水平与腺癌侵袭性呈正相关。在 20 个检查的临床肺癌标本中均观察到 YBX1 表达，其中 6 个标本的染色模式与 CERS6 相似。本研究结果提示转录因子 CEBPγ 和 YBX1 的可能参与促进肺癌迁移。
