Triptonide inhibits the pathological functions of gastric cancer-associated fibroblasts
Triptonide inhibits the pathological functions of gastric cancer-associated fibroblasts
复制标题
雷公藤奈德抑制胃癌相关成纤维细胞的病理功能
DOI：
10.1016/j.biopha.2017.10.046
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发表时间：
2017-12-01
影响因子：
7.5
通讯作者：
Jia, Yongfeng
中科院分区：
文献类型：
--
作者：
Wang, Zhenfei;Ma, Daguang;Jia, Yongfeng
化疗药物直接攻击肿瘤细胞具有加速肿瘤转移和诱导肿瘤干细胞表型的缺点。抑制肿瘤相关的成纤维细胞为肿瘤细胞提供营养和支持，是一种新的、有前途的抗肿瘤策略。然而，目前缺乏有效的抗肿瘤相关成纤维细胞的药物。在本研究中，我们探讨了雷公藤内酯抑制肿瘤相关成纤维细胞病理功能的可能性。取胃正常成纤维细胞(GNF)和胃癌相关成纤维细胞(GCAF)。GCAF比GNFS具有更强的诱导胃癌细胞集落形成、迁移和侵袭的能力。雷公藤内酯醇处理强烈抑制GCAF的集落形成、迁移和侵袭促进能力。GCAF中microRNA-301a的表达高于GNFS，而microRNA-149的表达低于GNFS。雷公藤内酯显著下调GCAF中microRNA-301a的表达，上调microRNA-149的表达。MicroRNA表达平衡的重建增加了肿瘤抑制因子金属蛋白酶组织抑制因子2的产生和分泌，抑制了致癌因子IL-6的产生和分泌。此外，雷公藤内酯醇治疗取消了GCAF诱导胃癌细胞上皮-间充质转化的能力。这些结果表明，雷公藤内酯醇通过纠正microRNA表达的异常而抑制GCAF的促癌能力。因此，雷公藤内酯是一种有希望的治疗胃癌的药物，而传统草药可能是开发调节肿瘤微环境的新药的有价值的来源。
Direct attacks on tumour cells with chemotherapeutic drugs have the drawbacks of accelerating tumour metastasis and inducing tumour stem cell phenotypes. Inhibition of tumour-associated fibroblasts, which provide nourishment and support to tumour cells, is a novel and promising anti-tumour strategy. However, effective drugs against tumour-associated fibroblasts are currently lacking. In the present study, we explored the possibility of inhibiting the pathological functions of tumour-associated fibroblasts with triptonide. Paired gastric normal fibroblasts (GNFs) and gastric cancer-associated fibroblasts (GCAFs) were obtained from resected tissues. GCAFs showed higher capacities to induce colony formation, migration, and invasion of gastric cancer cells than GNFs. Triptonide treatment strongly inhibited the colony formation-, migration-, and invasion-promoting capacities of GCAFs. The expression of microRNA-301a was higher and that of microRNA-149 was lower in GCAFs than in GNFs. Triptonide treatment significantly down-regulated microRNA-301a expression and up-regulated microRNA-149 expression in GCAFs. Re-establishment of microRNA expression balance increased the production and secretion of tissue inhibitor of metalloproteinase 2, a tumour suppressive factor, and suppressed the production and secretion of IL-6, an oncogenic factor, in GCAFs. Moreover, triptonide treatment abolished the ability of GCAFs to induce epithelial-mesenchymal transition in gastric cancer cells. These results indicate that triptonide inhibits the malignancy-promoting capacity of GCAFs by correcting abnormalities in microRNA expression. Thus, triptonide is a promisingly therapeutic agent for gastric cancer treatment, and traditional herbs may be a valuable source for developing new drugs that can regulate the tumour microenvironment.