The First Hospital of Lanzhou University, Lanzhou, China; The First Clinical Medical College of Lanzhou University, Lanzhou, China; Evidence Based Medicine Center, School of Basic Medical Science of Lanzhou University, Lanzhou, 730000, China; Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China; School of Nursing, Zunyi Medical University, Zunyi, China.
Evidence Based Medicine Center, School of Basic Medical Science of Lanzhou University, Lanzhou, 730000, China; Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China; Department of Computational Physics, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China; School of Nuclear Science and Technology, University of Chinese Academy of Sciences, Beijing, China.
Biomed Pharmacother. 2020 Apr;124:109838. doi: 10.1016/j.biopha.2020.109838. Epub 2020 Jan 22.
Hepatocellular carcinoma (HCC) is a malignant primary liver cancer with poor prognosis. Most previous studies on anti-HCC effects of traditional Chinese medicines (TCM) have focused on the mechanism of direct action and few researchers considered that TCM can inhibit tumor progression and improve prognosis of HCC patients through regulating tumor microenvironment (TME). In this study, network pharmacology combined bioinformatics methods were employed to analysis mechanism of Bombyx batryticatus (B. batryticatus, one of the most frequently used traditional Chinese animal medicines, has been used in some Asian countries for centuries as an anticancer agent, anti-inflammatory agent, and antioxidant.) in regulating TME of HCC. The results showed that 24 core targets and 2 compounds were identified from overlapping between differential expression genes related to HCC in the cancer genome atlas (TCGA) database and targets of B. batryticatus in TCMSP database. For further analyzing the role of TME heterogeneity of HCC on anti-HCC mechanism of B. batryticatus, the correlation of core targets related with overall survival of HCC with TME cells in hepatitis C or hepatitis B virus-associated hepatocellular carcinoma (VIR) and non-hepatitis C or hepatitis B virus-associated hepatocellular carcinoma (NVIR) were calculated, respectively. The results showed that AKR1C3, SPP1 were significantly related with macrophages in VIR and other targets including NR1I2, CYP1A2 and CYP3A4 were significantly associated with macrophages in NVIR; the target protein AKR1C3 was significantly negative correlated with macrophages M1 in VIR (cor=-0.35, P-value<0.001) and the correlation between AKR1C3 and macrophages M1 was poor in NVIR group (cor = 0.064, P-value = 0.36). Additionally, survival curve of AKR1C3 showed that poor prognosis in VIR group can be related to high level of AKR1C3 (HR = 2.32, 95 % CI: 1.18-4.56, P-value = 0.012), and no signified gene can be found in NVIR group (P-value>0.05). In conclusion, the molecular mechanism of anti-HCC of B. batryticatus can be related to the tumor microenvironment to some extent. B. batryticatus may exert its anti-cancer effects and improve prognosis of patients by regulating macrophages M1 in VIR and NVIR through acting on different targets.
肝细胞癌（HCC）是一种恶性原发性肝癌，预后不良。大多数先前关于中药（TCM）抗 HCC 作用的研究都集中在直接作用的机制上，很少有研究人员认为 TCM 可以通过调节肿瘤微环境（TME）来抑制肿瘤进展和改善 HCC 患者的预后。在这项研究中，采用网络药理学结合生物信息学方法分析了蚕茧（B. batryticatus，一种最常用的传统中药动物药，几个世纪以来一直被亚洲国家用作抗癌药、抗炎药和抗氧化剂）调节 HCC 的 TME 的机制。结果表明，从癌症基因组图谱（TCGA）数据库中与 HCC 相关的差异表达基因与 TCMSP 数据库中 B. batryticatus 的靶标之间重叠，鉴定出 24 个核心靶标和 2 种化合物。为了进一步分析 HCC 的 TME 异质性对 B. batryticatus 抗 HCC 机制的作用，计算了与 HCC 总体生存率相关的核心靶标与丙型肝炎或乙型肝炎病毒相关肝细胞癌（VIR）和非丙型肝炎或乙型肝炎病毒相关肝细胞癌（NVIR）中 TME 细胞的相关性。结果表明，AKR1C3、SPP1 与 VIR 中的巨噬细胞显著相关，其他靶标包括 NR1I2、CYP1A2 和 CYP3A4 与 NVIR 中的巨噬细胞显著相关；靶蛋白 AKR1C3 与 VIR 中的巨噬细胞 M1 呈显著负相关（cor=-0.35，P 值<0.001），在 NVIR 组中 AKR1C3 与巨噬细胞 M1 的相关性较差（cor=0.064，P 值=0.36）。此外，AKR1C3 的生存曲线表明，VIR 组中预后不良可能与 AKR1C3 水平升高有关（HR=2.32，95%CI：1.18-4.56，P 值=0.012），而在 NVIR 组中未发现显著基因（P 值>0.05）。总之，蚕茧抗 HCC 的分子机制在某种程度上可能与肿瘤微环境有关。蚕茧可能通过作用于不同的靶点，调节 VIR 和 NVIR 中的巨噬细胞 M1，发挥其抗癌作用并改善患者预后。
