Wang Kexin, Ye Xiangmin, Yin Chuanhui, Ren Qing, Chen Yupeng, Qin Xuemei, Duan Chuanzhi, Lu Aiping, Gao Li, Guan Daogang
National Key Clinical Specialty/Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Neurosurgery Institute, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Institute of Integrated Bioinformedicine and Translational Science, Hong Kong Baptist University, Hong Kong SAR, China.
Front Cell Dev Biol. 2022 Jul 22;10:859236. doi: 10.3389/fcell.2022.859236. eCollection 2022.
Hepatocellular carcinoma (HCC) is a complex issue in cancer treatment in the world at present. Matrine is the main active ingredient isolated from air and possesses excellent antitumor effects in HCC. However, the specific underlying mechanisms, especially the possible relationships between the anti-HCC effect of matrine and the related metabolic network of HCC, are not yet clear and need further clarification. In this study, an integrative metabolomic-based bioinformatics algorithm was designed to explore the underlying mechanism of matrine on HCC by regulating the metabolic network. Cell clone formation, invasion, and adhesion assay were utilized in HCC cells to evaluate the anti-HCC effect of matrine. A cell metabolomics approach based on LC-MS was used to obtain the differential metabolites and metabolic pathways regulated by matrine. The maximum activity contribution score model was developed and applied to calculate high contribution target genes of matrine, which could regulate a metabolic network based on the coexpression matrix of matrine-regulated metabolic genes and targets. Matrine significantly repressed the clone formation and invasion, enhanced cell-cell adhesion, and hampered cell matrix adhesion in SMMC-7721 cells. Metabolomics results suggested that matrine markedly regulated the abnormal metabolic network of HCC by regulating the level of choline, creatine, valine, spermidine, 4-oxoproline, D-(+)-maltose, L-(-)-methionine, L-phenylalanine, L-pyroglutamic acid, and pyridoxine, which are involved in D-glutamine and D-glutamate metabolism, glycine, serine and threonine metabolism, arginine and proline metabolism, etc. Our proposed metabolomic-based bioinformatics algorithm showed that the regulating metabolic networks of matrine exhibit anti-HCC effects through acting on MMP7, ABCC1, PTGS1, etc. At last, MMP7 and its related target -catenin were validated. Together, the metabolomic-based bioinformatics algorithm reveals the effects of the regulating metabolic networks of matrine in treating HCC relying on the unique characteristics of the multitargets and multipathways of traditional Chinese medicine.
肝细胞癌（HCC）是目前全球癌症治疗中的一个复杂问题。苦参碱是从苦参中分离出的主要活性成分，对HCC具有优异的抗肿瘤作用。然而，其具体的潜在机制，尤其是苦参碱抗HCC作用与HCC相关代谢网络之间可能的关系，尚不清楚，需要进一步阐明。在本研究中，设计了一种基于整合代谢组学的生物信息学算法，以通过调节代谢网络来探索苦参碱对HCC的潜在作用机制。利用HCC细胞的细胞克隆形成、侵袭和黏附试验来评估苦参碱的抗HCC作用。采用基于液相色谱-质谱联用（LC-MS）的细胞代谢组学方法来获取受苦参碱调节的差异代谢物和代谢途径。开发并应用最大活性贡献得分模型来计算苦参碱的高贡献靶基因，该模型可基于苦参碱调节的代谢基因和靶标的共表达矩阵来调节代谢网络。苦参碱显著抑制SMMC-7721细胞的克隆形成和侵袭，增强细胞间黏附，并阻碍细胞与基质的黏附。代谢组学结果表明，苦参碱通过调节胆碱、肌酸、缬氨酸、亚精胺、4-氧代脯氨酸、D-（+）-麦芽糖、L-（-）-甲硫氨酸、L-苯丙氨酸、L-焦谷氨酸和吡哆醇的水平，显著调节HCC异常的代谢网络，这些代谢物参与D-谷氨酰胺和D-谷氨酸代谢、甘氨酸、丝氨酸和苏氨酸代谢、精氨酸和脯氨酸代谢等。我们提出的基于代谢组学的生物信息学算法表明，苦参碱调节的代谢网络通过作用于基质金属蛋白酶7（MMP7）、ATP结合盒转运蛋白C1（ABCC1）、前列腺素内过氧化物合酶1（PTGS1）等发挥抗HCC作用。最后，对MMP7及其相关靶点β-连环蛋白进行了验证。总之，基于代谢组学的生物信息学算法揭示了苦参碱调节的代谢网络在治疗HCC中的作用，这依赖于中药多靶点和多途径的独特特性。
