AUTHOR=Wei Chaoguang , Zhao Yuxiang , Ji Tao , Sun Yong , Cai Xudong , Peng Xin 

TITLE=Cyclin-Dependent Kinase 6 Identified as the Target Protein in the Antitumor Activity of Tetrastigma hemsleyanum

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.865409

DOI=10.3389/fonc.2022.865409

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p><italic>Tetrastigma hemsleyanum</italic> (<italic>T. hemsleyanum</italic>) is widely used as an adjuvant drug for tumor therapy but its antitumor therapeutic targets and molecular mechanisms have remained unclear. The prediction and analysis of natural products has previously used only network pharmacology methods to identify potential target proteins from public databases. In this study, we use comprehensive bioinformatics analysis and experimental verification to determine the antitumor mechanism of <italic>T. hemsleyanum</italic>.</p></sec><sec><title>Methods</title><p>Network pharmacology analysis was used to predict the potential <italic>in vivo</italic> target proteins of <italic>T. hemsleyanum</italic>. The expression matrix and clinical data to perform an analysis of hub genes were collected from the TCGA and GTEx databases, specifically the analysis of expression, prognosis, tumor immune cell infiltration analysis, immune checkpoint genes, microsatellite instability, tumor mutational burden, tumor neoantigen, and immune microenvironment, which identify the roles and biological functions of the hub genes in pan-cancer. Finally, gene set enrichment analysis was used to verify the biological processes and signaling pathways involved in the pan-cancer expression profile.</p></sec><sec><title>Results</title><p>We found 124 potential <italic>in vivo</italic> target proteins of <italic>T. hemsleyanum</italic> through network pharmacological analysis, and five hub genes (AKR1C1, MET, PTK2, PIK3R1, and CDK6) were then screened by protein–protein interaction (PPI) network analysis and molecular complex detection analysis (MCODE). Experimental intervention with an aqueous extract of <italic>T. hemsleyanum</italic> verified that these hub genes are the target proteins involved in the regulation of <italic>T. hemsleyanum</italic> in cells. A pan-cancer analysis then confirmed that CDK6 and MET are potential targets upon which <italic>T. hemsleyanum</italic> may exert antitumor action, especially in ACC, CESC, LGG, and PAAD. The CDK6 protein targeted by <italic>T. hemsleyanum</italic> is also involved in the immune and mutation process of pan-cancer, especially in the regulation of immune cell infiltration, immune checkpoint gene expression, microsatellite instability, tumor mutation burdens, and tumor neoantigens. Together, these analyses show that <italic>T. hemsleyanum</italic> affects tumor immune regulation and genomic stability. Finally, a gene set enrichment analysis confirmed that <italic>T. hemsleyanum</italic> regulates the cell cycle checkpoint.</p></sec><sec><title>Conclusions</title><p>We found that <italic>T. hemsleyanum</italic> can behave as an antitumor agent by acting as a potential cell cycle checkpoint inhibitor in CDK6-driven tumors, such as ACC, CESC, LGG, and PAAD, and that it acts as a tyrosine kinase receptor inhibitor that inhibits the expression of the proto-oncogene MET. Combined with an analysis of immune and mutation correlations in pan-cancer, we determined that <italic>T. hemsleyanum</italic> may function biologically as an immune regulator and interfere with the stability of the tumor genome, which is worthy of further study.</p></sec>