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Abstract：
Transforming growth factor-β (TGF-β) signaling pathway serves a pivotal role in the pathogenesis of colorectal cancer (CRC). However, the specific molecular mechanisms by which the TGF-β signaling pathway regulates CRC are still not fully understood. In the present study, metabolomics and transcriptomics were used to screen for key metabolites and regulatory genes most related to the regulation of the TGF-β signaling pathway in CRC. Additionally, reverse transcription-quantitative PCR, western blotting and Transwell assays were performed to assess the process of epithelial-mesenchymal transition (EMT). Metabolomics analysis indicated that TGF-β1 has an impact on purine metabolism, leading to an increase in the purine metabolite inosine. The increase of inosine is essential for facilitating EMT and cell migration in CRC cells. Furthermore, the integrated analysis of metabolomics and transcriptomics data revealed that TGF-β1 induces the expression of laccase domain-containing 1 (LACC1), an enzyme involved in the regulation of inosine. Knockdown of LACC1 resulted in a reduction of TGF-β1-induced alterations in inosine levels, EMT and cell migration in CRC cells. The results of the present study suggest that the TGF-β signaling pathway is involved in the regulation of purine metabolism in CRC through the modulation of LACC1 expression. Furthermore, LACC1 appears to influence EMT and cell migration by elevating the levels of the purine metabolite inosine.
摘要：
转化生长因子-β（TGF-β）信号通路在结直肠癌（CRC）的发病机制中起着关键作用。然而,TGF-β信号通路调控CRC的具体分子机制尚不完全清楚.在本研究中,代谢组学和转录组学用于筛选与CRC中TGF-β信号通路调控最相关的关键代谢物和调控基因.此外,逆转录-定量PCR,进行蛋白质印迹和Transwell测定以评估上皮-间质转化（EMT）的过程。代谢组学分析表明TGF-β1对嘌呤代谢有影响,导致嘌呤代谢物肌苷增加。肌苷的增加对于促进CRC细胞中的EMT和细胞迁移至关重要。此外，代谢组学和转录组学数据的综合分析显示，TGF-β1诱导含有漆酶结构域1（LACC1）的表达，一种参与肌苷调节的酶。敲除LACC1导致TGF-β1诱导的肌苷水平改变减少，CRC细胞中的EMT和细胞迁移。本研究的结果表明，TGF-β信号通路通过调节LACC1的表达参与了CRC嘌呤代谢的调节。此外，LACC1似乎通过提高嘌呤代谢物肌苷的水平来影响EMT和细胞迁移。
