Zhao Fulai, Zhao Peng, Chang Junli, Sun Xingyuan, Ma Xiaoping, Shi Binhao, Yin Mengchen, Wang Yongjun, Yang Yanping
Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai, China.
Front Genet. 2023 Feb 7;14:1112671. doi: 10.3389/fgene.2023.1112671. eCollection 2023.
Lung adenocarcinoma (LUAD) is the main histological type of lung cancer with an unfavorable survival rate. Metastasis is the leading LUAD-related death with Epithelial-Mesenchymal Transition (EMT) playing an essential role. The anticancer efficacies of the active ingredients in Chonglou have been widely reported in various cancers. However, the potential therapeutic targets of the Chonglou active ingredients in LUAD patients remain unknown. Here, the network pharmacology and bioinformatics were performed to analyze the associations of the clinical characteristics, immune infiltration factors and mA-related genes with the EMT-related genes associated with LUAD (EMT-LUAD related genes), and the molecular docking, STRING, GO, and KEGG enrichment for the drug targets of Chonglou active ingredients associated with EMT (EMT-LUAD-Chonglou related genes). And, cell viability analysis and cell invasion and infiltration analysis were used to confirm the theoretical basis of this study. A total of 166 EMT-LUAD related genes were identified and a multivariate Cox proportional hazards regression model with a favorable predictive accuracy was constructed. Meanwhile, the immune cell infiltration, immune cell subsets, checkpoint inhibitors and the expression of mA-related genes were significantly associated with the risk scores for EMT-LUAD related genes with independent significant prognostic value of all included LUAD patients. Furthermore, 12 EMT-LUAD-Chonglou related genes with five core drug targets were identified, which participated in LUAD development through extracellular matrix disassembly, collagen metabolic process, collagen catabolic process, extracellular matrix organization, extracellular structure organization and inflammatory response. Moreover, we found that the active ingredients of Chonglou could indeed inhibit the progression of lung adenocarcinoma cells. These results are oriented towards EMT-related genes to achieve a better understanding of the role of Chonglou and its targets in osteosarcoma development and metastasis, thus guiding future preclinical studies and facilitating clinical translation of LUAD treatment.
肺腺癌（LUAD）是肺癌的主要组织学类型，生存率较低。转移是导致LUAD相关死亡的主要原因，上皮-间质转化（EMT）在其中起着至关重要的作用。重楼中活性成分的抗癌功效已在多种癌症中得到广泛报道。然而，重楼活性成分在LUAD患者中的潜在治疗靶点仍不清楚。在此，运用网络药理学和生物信息学分析临床特征、免疫浸润因子和mA相关基因与LUAD相关的EMT相关基因（EMT-LUAD相关基因）之间的关联，以及重楼活性成分与EMT相关的药物靶点（EMT-LUAD-重楼相关基因）的分子对接、STRING、GO和KEGG富集分析。并且，通过细胞活力分析以及细胞侵袭和浸润分析来证实本研究的理论基础。共鉴定出166个EMT-LUAD相关基因，并构建了具有良好预测准确性的多变量Cox比例风险回归模型。同时，免疫细胞浸润、免疫细胞亚群、检查点抑制剂以及mA相关基因的表达与EMT-LUAD相关基因的风险评分显著相关，对所有纳入的LUAD患者具有独立的显著预后价值。此外，鉴定出12个EMT-LUAD-重楼相关基因及5个核心药物靶点，它们通过细胞外基质分解、胶原代谢过程、胶原分解代谢过程、细胞外基质组织、细胞外结构组织和炎症反应参与LUAD的发展。而且，我们发现重楼的活性成分确实可以抑制肺腺癌细胞的进展。这些结果以EMT相关基因为导向，以更好地理解重楼及其靶点在骨肉瘤发生和转移中的作用，从而指导未来的临床前研究并促进LUAD治疗的临床转化。
