N-methylnicotinamide and nicotinamide N-methyltransferase are associated with microRNA-1291-altered pancreatic carcinoma cell metabolome and suppressed tumorigenesis
N-methylnicotinamide and nicotinamide N-methyltransferase are associated with microRNA-1291-altered pancreatic carcinoma cell metabolome and suppressed tumorigenesis
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DOI：
10.1093/carcin/bgu174
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发表时间：
2014-10-01
期刊：
影响因子：
4.7
通讯作者：
Yu, Ai-Ming
中科院分区：
文献类型：
--
作者：
Bi, Hui-Chang;Pan, Yu-Zhuo;Yu, Ai-Ming
细胞代谢物组包含丰富的信息，其可以预测响应于细胞增殖和转移的不同阶段的表观遗传或遗传变化的细胞功能。一项基于超高效液相色谱-质谱的无偏代谢组学研究显示，具有功能获得性非编码microRNA-1291（miR-1291）的人胰腺癌PANC-1细胞的代谢组发生了显著改变，这导致了异种移植肿瘤小鼠模型中迁移和侵袭能力的降低以及肿瘤发生的抑制。许多代谢物，包括参与烟酰胺代谢的N-甲基烟酰胺，以及参与脂肪酸代谢的l-肉毒碱、异丁酰肉毒碱和异戊酰肉毒碱，在表达miR-1291的PANC-1中升高。值得注意的是，N-甲基烟酰胺最大程度地升高，这与表达miR-1291的PANC-1细胞中烟酰胺N-甲基转移酶（NNMT）mRNA水平的急剧增加相关。此外，在异种移植小鼠模型中，NNMT mRNA的表达与胰腺肿瘤大小呈负相关。这些结果表明，miR-1291改变的PANC-1细胞功能与N-甲基烟酰胺水平和NNMT表达的增加相关，反过来NNMT可能指示胰腺癌发生的程度。
The cell metabolome comprises abundant information that may be predictive of cell functions in response to epigenetic or genetic changes at different stages of cell proliferation and metastasis. An unbiased ultra-performance liquid chromatography-mass spectrometry-based metabolomics study revealed a significantly altered metabolome for human pancreatic carcinoma PANC-1 cells with gain-of-function non-coding microRNA-1291 (miR-1291), which led to a lower migration and invasion capacity as well as suppressed tumorigenesis in a xenograft tumor mouse model. A number of metabolites, including N-methylnicotinamide, involved in nicotinamide metabolism, and l-carnitine, isobutyryl-carnitine and isovaleryl-carnitine, involved in fatty acid metabolism, were elevated in miR-1291-expressing PANC-1. Notably, N-methylnicotinamide was elevated to the greatest extent, and this was associated with a sharp increase in nicotinamide N-methyltransferase (NNMT) mRNA level in miR-1291-expressing PANC-1 cells. In addition, expression of NNMT mRNA was inversely correlated with pancreatic tumor size in the xenograft mouse model. These results indicate that miR-1291-altered PANC-1 cell function is associated with the increase in N-methylnicotinamide level and NNMT expression, and in turn NNMT may be indicative of the extent of pancreatic carcinogenesis.