Cao Lianlian, Li Zhaoping, Huang Yibo, Chen Hao, Chen Li, Tao Liang, Wang Meng, Tao Tingting, Wang Feng
Division of Gastric Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Drum Tower Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China.
Division of Gastric Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Drum Tower Clinical Medical College, Nanjing Medical University, Nanjing, China.
J Ethnopharmacol. 2025 Feb 27;342:119389. doi: 10.1016/j.jep.2025.119389. Epub 2025 Jan 22.
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the digestive tract, often accompanied by a high risk of recurrence and drug resistance. Huaier (Trametes robiniophila Murr), a traditional Chinese medicinal fungus, has demonstrated potent anticancer properties and is widely used as an adjuvant treatment for liver, breast, gastric, colon, and non-small cell lung cancers. However, its effects and molecular mechanisms in GIST remain unclear.
This study aims to explore the inhibitory effects and underlying mechanisms of Huaier on GIST through network pharmacology and experimental validation.
Initially, we utilized a publicly accessible database to identify the core targets and principal pathways associated with Huaier's therapeutic effects on gastrointestinal stromal tumors. To further evaluate its biological impact, cell viability, proliferation, migration, and invasion were assessed through CCK-8 and EdU assays, wound healing tests, and Transwell experiments. Apoptotic cell death was quantified using flow cytometry analysis. Additionally, the influence of Huaier extract on the expression levels of JAK2 and STAT3 proteins was examined via Western blotting. Finally, a subcutaneous xenograft mouse model was employed to investigate the anti-tumor efficacy of Huaier in vivo.
In this study, GAPDH, TNF, STAT3, ESR1, EGFR, IL6, CCND1, PTGS2, BCL2L1, and MAPK3 were identified as shared molecular targets, with the JAK/STAT signaling pathway recognized as the pivotal regulatory mechanism. Experimental findings demonstrated that Huaier exerted inhibitory effects on the proliferation, migration, and invasion of GIST-T1 and GIST-882 cells, exhibiting both dose- and time-dependent responses. Furthermore, Huaier was found to promote apoptosis in these cells. Western blot analysis revealed that treatment with Huaier extract significantly decreased the phosphorylation levels of JAK2 and STAT3, thereby suppressing the activation of the JAK2/STAT3 signaling cascade. In vivo experiments further substantiated these findings, showing that Huaier treatment markedly reduced tumor size and inhibited tumor progression.
Our results suggest that Huaier may inhibit the growth of GIST cells by inhibiting the JAK2/STAT3 signaling pathway, reduce cell proliferation, induce apoptosis, reduce cell migration and invasion, and show anti-tumor effects in vivo and in vitro.
胃肠道间质瘤（GIST）是消化道最常见的间充质肿瘤，常伴有高复发风险和耐药性。槐耳（Trametes robiniophila Murr），一种传统的药用真菌，已显示出强大的抗癌特性，被广泛用作肝癌、乳腺癌、胃癌、结肠癌和非小细胞肺癌的辅助治疗药物。然而，其在胃肠道间质瘤中的作用和分子机制仍不清楚。
本研究旨在通过网络药理学和实验验证，探讨槐耳对胃肠道间质瘤的抑制作用及其潜在机制。
首先，我们利用一个公开可用的数据库，确定与槐耳对胃肠道间质瘤治疗作用相关的核心靶点和主要途径。为了进一步评估其生物学影响，通过CCK-8和EdU试验、伤口愈合试验和Transwell实验评估细胞活力、增殖、迁移和侵袭。使用流式细胞术分析对凋亡细胞死亡进行定量。此外，通过蛋白质印迹法检测槐耳提取物对JAK2和STAT3蛋白表达水平的影响。最后，采用皮下异种移植小鼠模型研究槐耳在体内的抗肿瘤疗效。
在本研究中，GAPDH、TNF、STAT3、ESR1、EGFR、IL6、CCND1、PTGS2、BCL2L1和MAPK3被确定为共同的分子靶点，JAK/STAT信号通路被认为是关键的调节机制。实验结果表明，槐耳对GIST-T1和GIST-882细胞的增殖、迁移和侵袭具有抑制作用，呈现出剂量和时间依赖性反应。此外，发现槐耳可促进这些细胞凋亡。蛋白质印迹分析显示，用槐耳提取物处理可显著降低JAK2和STAT3的磷酸化水平，从而抑制JAK2/STAT3信号级联的激活。体内实验进一步证实了这些结果，表明槐耳治疗显著减小了肿瘤大小并抑制了肿瘤进展。
我们的结果表明，槐耳可能通过抑制JAK2/STAT3信号通路来抑制胃肠道间质瘤细胞的生长，减少细胞增殖，诱导凋亡，减少细胞迁移和侵袭，并在体内和体外均显示出抗肿瘤作用。
