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Systematically Exploring the Antitumor Mechanisms of Core Chinese Herbs on Hepatocellular Carcinoma: A Computational Study

ABSTRACT: Objective Chinese herbs play a positive role in the management of hepatocellular carcinoma (HCC) in China. However, it is not clear which of Chinese herbs are critical for the treatment of HCC. Besides, mechanisms of CCHs in the treatment of HCC remain unclear. Hence, our goal is to identify the core Chinese herbs (CCHs) for treating HCC and explore their antitumor mechanism. Methods Firstly, clinical traditional Chinese medicine (TCM) prescriptions for HCC were collected from Chinese National Knowledge Infrastructure (CNKI) database, and then, data mining software was used to identify CCHs. After that, bioactive compounds and corresponding target genes of CCHs were obtained using three TCM databases, and target genes of HCC were acquired from MalaCards and OMIM. Subsequently, common target genes of CCHs and HCC were screened. Moreover, biological functions and pathways were analyzed, and Cytoscape plugin cytoHubba was used to identify hub genes. Finally, prognostic values of hub genes were verified by survival analysis, and the molecular docking approach was utilized to validate the interactions between targets and bioactive compounds of CCHs. Results Eight CCHs were determined from 630 prescriptions, and 100 bioactive compounds (e.g., quercetin and luteolin) and 126 common target genes were screened. Furthermore, common target genes of CCHs and HCC were mainly enriched in cancer-associated pathways, and six hub genes with statistical significance in survival analysis were selected as key target genes for molecular docking. Additionally, molecular docking showed that the bioactive compounds docked well with the protein receptors of key target genes. Conclusion By combining data mining, network pharmacology, molecular docking, and survival analysis methods, we found that CCHs may play a therapeutic role in HCC through regulating the target genes and pathways related to cancer occurrence and development, angiogenesis, metastasis, and prognosis.

SUBMITTER: Wu Z

PROVIDER: S-EPMC7512071 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:Colorectal cancer (CRC) is now the second most deadly cancer globally. Chinese herbal medicine (CHM) plays an indispensable role in CRC treatment in China. However, the core herbs (the CHs) in the treatment of CRC and their underlying therapeutic mechanisms remain unclear. This study aims to uncovering the CHs and their mechanisms of action of CRC treatment, applying data mining and network pharmacology approach. First, CHM prescriptions treating CRC were collected from clinical studies from the Chinese National Knowledge Infrastructure (CNKI) and MEDLINE databases, and the CHs were identified through data mining. Then, the bioactive compounds and the corresponding putative targets of the CHs were obtained from three traditional Chinese medicine (TCM) databases. CRC related targets were acquired from three disease databases; the overlapping targets between the CHs and CRC were identified as the therapeutic targets. Subsequently, functional enrichment analysis was performed to elucidate the mechanisms of the CHs on CRC. Moreover, networks were constructed to screen the major bioactive compounds and therapeutic targets. Finally, prognostic values of the major target genes were evaluated by survival analysis, and molecular docking simulation was performed to assess the binding affinity of key targets and major bioactive compounds. It came out that 10 the CHs from 113 prescriptions and 190 bioactive compounds with 118 therapeutic targets were identified. The therapeutic targets were mainly enriched in the biological progress of transcription, apoptosis, and response to cytokine. Various cancer-associated signaling pathways, including microRNAs, TNF, apoptosis, PI3K-Akt, and p53, were involved. Furthermore, 15 major bioactive compounds and five key target genes (VEGFA, CASP3, MYC, CYP1Y1, and NFKB1) with prognostic significance were identified. Additionally, most major bioactive compounds might bind firmly to the key target proteins. This study provided an overview of the anti-CRC mechanisms of the CHs, which might refer to the regulation of apoptosis, transcription, and inflammation.

Project description:ObjectiveArsenic trioxide (Pishuang, Pishi, arsenolite, As2O3, and CAS 1327-53-3), a naturally occurring and toxic mineral as a drug for more than 2000 years in China, has been found to have a valuable function in hepatocellular carcinoma (HCC) in recent years. However, its exact mechanism remains to be elucidated. Therefore, this study was intended to explore the potential anti-HCC mechanism of arsenic trioxide through network pharmacology.MethodsThe potential targets of arsenic trioxide were collected from PubChem and TargetNet. HCC targets were obtained from the GeneCards database. Then, a protein-protein interaction (PPI) network of arsenic trioxide and HCC common targets was established using STRING. GO and KEGG pathway enrichment analyses were performed by the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Finally, an arsenic trioxide-target-pathway-HCC network was built by Cytoscape 3.2.1, and network topological analysis was carried out to screen the key candidate targets.ResultsA total of 346 corresponding targets of arsenic trioxide and 521 HCC-related targets were collected. After target mapping, a total of 52 common targets were obtained. GO analysis showed that the biological process was mainly involved in the negative regulation of cellular senescence, response to tumor necrosis factor, and cellular response to hypoxia. Molecular functions included NF-kappa B binding, enzyme binding, p53 binding, and transcription factor binding. Cellular components mainly were replication fork, ESC/E(Z) complex, RNA polymerase II transcription factor complex, and organelle membrane. KEGG pathways were mainly enriched in the PI3K-Akt signaling pathway, VEGF signaling pathway, p53 signaling pathway, HIF-1 signaling pathway, TNF signaling pathway, AMPK signaling pathway, NF-kappa B signaling pathway, FoxO signaling pathway, ErbB signaling pathway, and MAPK signaling pathway. In the arsenic trioxide-target-pathway-HCC network, targets such as AKT1, RAF1, RELA, TP53, and PTEN had a higher degree. Conclusions. Our study showed that key targets of arsenic trioxide were mainly involved in multiple biological processes and pathways. It provided a theoretical basis for the screening of drug targets.

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Systematically Exploring the Antitumor Mechanisms of Core Chinese Herbs on Hepatocellular Carcinoma: A Computational Study

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