PDF(Pubmed)
Abstract：
UNASSIGNED: Extramammary Paget\'s disease (EMPD) is a rare cutaneous malignancy, commonly affecting the external genitalia and perianal area of the elderly with unclear pathogenesis. Metabolomics provides a novel perspective for uncovering the metabolic mechanisms of a verity of cancers.
UNASSIGNED: Here, we explored the metabolome of EMPD using an untargeted strategy. In order to further investigate the potential relationship between metabolites and gene expression, we re-analyzed the gene expression microarray data (GSE117285) using differential expression analysis and functional enrichment analyses.
UNASSIGNED: Results showed that a total of 896 metabolites were identified and 87 metabolites including 37 upregulated and 50 downregulated significantly in EMPD were sought out. In the following feature selection analyses, four metabolites, namely, cyclopentyl fentanyl-d5, LPI 17:0, guanosine-3\',5\'-cyclic monophosphate, kynurenine (KYN, high in EMPD) were identified by both random forest and support vector machine analyses. We then identified 1,079 dysfunctional genes: 646 upregulated and 433 downregulated in EMPD. Specifically, the tryptophan-degrading enzyme including indoleamine-2,3-dioxygenase-1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) were also increased. Generally, cancers exhibit a high expression of IDO1 and TDO2 to catabolize tryptophan, generating abundant KYN. Moreover, we also noticed the abnormal activation of sustaining proliferative signaling in EMPD.
UNASSIGNED: In conclusion, this study was the first to reveal the metabolome profile of EMPD. Our results demonstrate that IDO1/TDO2-initialized KYN metabolic pathway may play a vital role in the development and progression of EMPD, which may serve as a potential therapeutic target for treating EMPD.
UNASSIGNED: Here, we explored the metabolome of EMPD using an untargeted strategy. In order to further investigate the potential relationship between metabolites and gene expression, we re-analyzed the gene expression microarray data (GSE117285) using differential expression analysis and functional enrichment analyses.
UNASSIGNED: Results showed that a total of 896 metabolites were identified and 87 metabolites including 37 upregulated and 50 downregulated significantly in EMPD were sought out. In the following feature selection analyses, four metabolites, namely, cyclopentyl fentanyl-d5, LPI 17:0, guanosine-3\',5\'-cyclic monophosphate, kynurenine (KYN, high in EMPD) were identified by both random forest and support vector machine analyses. We then identified 1,079 dysfunctional genes: 646 upregulated and 433 downregulated in EMPD. Specifically, the tryptophan-degrading enzyme including indoleamine-2,3-dioxygenase-1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) were also increased. Generally, cancers exhibit a high expression of IDO1 and TDO2 to catabolize tryptophan, generating abundant KYN. Moreover, we also noticed the abnormal activation of sustaining proliferative signaling in EMPD.
UNASSIGNED: In conclusion, this study was the first to reveal the metabolome profile of EMPD. Our results demonstrate that IDO1/TDO2-initialized KYN metabolic pathway may play a vital role in the development and progression of EMPD, which may serve as a potential therapeutic target for treating EMPD.
摘要：
■乳腺外Paget病（EMPD）是一种罕见的皮肤恶性肿瘤，常累及外生殖器和肛周区域的老年人，发病机制不明确。代谢组学为揭示癌症的代谢机制提供了新的视角。
■这里，我们使用非靶向策略探索了EMPD的代谢组。为了进一步研究代谢物与基因表达之间的潜在关系，我们使用差异表达分析和功能富集分析重新分析了基因表达微阵列数据(GSE117285).
■结果表明，总共鉴定出896种代谢物，并在EMPD中找到了87种代谢物，包括37种上调和50种下调。在以下特征选择分析中，四种代谢物，即,环戊基芬太尼-d5，LPI17：0，鸟苷-3'，5'-环单磷酸酯，犬尿氨酸(KYN,EMPD较高)是通过随机森林和支持向量机分析确定的。然后我们鉴定了1,079个功能失调的基因:在EMPD中646个上调和433个下调。具体来说,色氨酸降解酶，包括吲哚胺-2,3-双加氧酶-1（IDO1）和色氨酸2,3-双加氧酶（TDO2）也增加。一般来说,癌症表现出IDO1和TDO2的高表达以分解代谢色氨酸，产生丰富的KYN。此外，我们还注意到EMPD中持续增殖信号的异常激活。
■总而言之，这项研究首次揭示了EMPD的代谢组特征。我们的结果表明，IDO1/TDO2初始化的KYN代谢途径可能在EMPD的发生和发展中起着至关重要的作用。它可以作为治疗EMPD的潜在治疗靶点。
■这里，我们使用非靶向策略探索了EMPD的代谢组。为了进一步研究代谢物与基因表达之间的潜在关系，我们使用差异表达分析和功能富集分析重新分析了基因表达微阵列数据(GSE117285).
■结果表明，总共鉴定出896种代谢物，并在EMPD中找到了87种代谢物，包括37种上调和50种下调。在以下特征选择分析中，四种代谢物，即,环戊基芬太尼-d5，LPI17：0，鸟苷-3'，5'-环单磷酸酯，犬尿氨酸(KYN,EMPD较高)是通过随机森林和支持向量机分析确定的。然后我们鉴定了1,079个功能失调的基因:在EMPD中646个上调和433个下调。具体来说,色氨酸降解酶，包括吲哚胺-2,3-双加氧酶-1（IDO1）和色氨酸2,3-双加氧酶（TDO2）也增加。一般来说,癌症表现出IDO1和TDO2的高表达以分解代谢色氨酸，产生丰富的KYN。此外，我们还注意到EMPD中持续增殖信号的异常激活。
■总而言之，这项研究首次揭示了EMPD的代谢组特征。我们的结果表明，IDO1/TDO2初始化的KYN代谢途径可能在EMPD的发生和发展中起着至关重要的作用。它可以作为治疗EMPD的潜在治疗靶点。
