High CerS5 expression levels associate with reduced patient survival and transition from apoptotic to autophagy signalling pathways in colorectal cancer.
High CerS5 expression levels associate with reduced patient survival and transition from apoptotic to autophagy signalling pathways in colorectal cancer.
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DOI：
10.1002/cjp2.5
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发表时间：
2015-01
期刊：
影响因子：
--
通讯作者：
Kijanka GS
中科院分区：
文献类型：
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作者：
Fitzgerald S;Sheehan KM;Espina V;O'Grady A;Cummins R;Kenny D;Liotta L;O'Kennedy R;Kay EW;Kijanka GS
神经酰胺合成酶5参与神经酰胺的从头合成，神经酰胺是一种神经鞘磷脂，参与细胞的死亡和增殖。在本研究中，我们通过检测神经酰胺合成酶5在结直肠癌中的表达、临床病理参数以及与生存/死亡信号通路的关系，探讨神经酰胺合成酶5在结直肠癌中的作用。应用由福尔马林固定和石蜡包埋组织构建的组织芯片，对102例结直肠癌标本进行CerS5免疫组织化学分析。我们发现在102例结直肠癌中有57例(56%)膜神经酰胺合成酶5染色很强。对神经酰胺合成酶5表达的多因素COX回归分析表明，调整了疾病分期、分化程度和淋巴血管侵犯后，5年总生存率(p = 0.001)和5年无复发生存率(p = 0.002)降低，风险比分别为4.712和4.322。神经酰胺合成酶5的表达对肿瘤发生过程的影响进一步通过反相蛋白质阵列分析来表征。反相蛋白质阵列是从19个新鲜的结直肠癌组织的激光捕获显微切割浓缩的癌细胞中产生的。对参与细胞凋亡、自噬和其他癌症相关途径的信号蛋白的磷酸化和总水平的测量揭示了两个不同的信号网络：弱的膜性神经酰胺合成酶5强度与由与凋亡相关的信号蛋白主导的蛋白质组网络有关，而强的神经酰胺合成酶5强度与主要由与自噬相关的蛋白质组成的蛋白质组亚网络有关。总之，在结直肠癌组织中发现神经酰胺合成酶5的高表达，并与较差的患者预后相关。我们的研究结果表明，神经酰胺合成酶5高表达的肿瘤中，神经酰胺合成酶5的高表达可能通过从凋亡信号通路向自噬信号通路的转变来调节，从而暗示神经酰胺合成酶5在结直肠癌的进展中起作用。
Ceramide synthase 5 is involved in the de novo synthesis of ceramide, a sphingolipid involved in cell death and proliferation. In this study, we investigated the role of ceramide synthase 5 in colorectal cancer by examining ceramide synthase 5 expression, clinico‐pathological parameters and association with survival/death signalling pathways in cancer. Immunohistochemical analysis of CerS5 was performed on 102 colorectal cancer samples using tissue microarrays constructed from formalin‐fixed and paraffin‐embedded tissues. We found strong membranous ceramide synthase 5 staining in 57 of 102 (56%) colorectal cancers. A multivariate Cox regression analysis of ceramide synthase 5 expression adjusted for disease stage, differentiation and lymphovascular invasion revealed reduced 5‐year overall survival (p = 0.001) and 5‐year recurrence‐free survival (p = 0.002), with hazard ratios of 4.712 and 4.322, respectively. The effect of ceramide synthase 5 expression on tumourigenic processes was further characterised by reverse phase protein array analysis. Reverse phase protein arrays were generated from laser capture microdissection‐enriched carcinoma cells from 19 fresh‐frozen colorectal cancer tissues. Measurements of phosphorylation and total levels of signalling proteins involved in apoptosis, autophagy and other cancer‐related pathways revealed two distinct signalling networks; weak membranous ceramide synthase 5 intensity was associated with a proteomic network dominated by signalling proteins linked to apoptosis, whereas strong ceramide synthase 5 intensity was associated with a proteomic sub‐network mostly composed of proteins linked to autophagy. In conclusion, high ceramide synthase 5 expression was found in colorectal cancer tissue and was associated with poorer patient outcomes. Our findings suggest that this may be mediated by a transition from apoptotic to autophagy signalling pathways in ceramide synthase 5 High expressing tumours, thus implicating ceramide synthase 5 in the progression of colorectal cancer.