Zoledronic acid inhibits thyroid cancer stemness and metastasis by repressing M2-like tumor-associated macrophages induced Wnt/β-catenin pathway
Zoledronic acid inhibits thyroid cancer stemness and metastasis by repressing M2-like tumor-associated macrophages induced Wnt/β-catenin pathway
复制标题
唑来膦酸通过抑制 M2 样肿瘤相关巨噬细胞诱导的 Wnt/β-连环蛋白途径来抑制甲状腺癌干性和转移
DOI：
10.1016/j.lfs.2020.117925
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发表时间：
2020-09-01
期刊：
影响因子：
6.1
通讯作者：
Deng, Zhi-Yong
中科院分区：
文献类型：
--
作者：
Lv, Juan;Chen, Fu-Kun;Deng, Zhi-Yong
目的：本研究旨在探讨唑来膦酸（zoledronic acid，ZA）对甲状腺癌（Thyroid cancer，TC）发生的影响及其可能机制，材料和方法：人单核细胞THP-1经PMA诱导分化为M2样肿瘤相关巨噬细胞（Tumor associated macrophages，TAMs），再经IL-4和IL-13诱导分化。TC细胞TPC-1和IHH 4与M2样TAM共培养。通过免疫组织化学或流式细胞术确定M2样TAM标志物的鉴定。分别采用集落形成法、球体形成法和transwell法检测细胞增殖、干细胞和迁移/侵袭能力。通过qRT-PCR、Western印迹和免疫荧光验证细胞干细胞性、EMT和Wnt/β-连环蛋白通路相关因子的表达水平。结果：在TC组织中，M2样TAM富集，促进殖民地/球体形成，并下调TC细胞中E-cadherin的表达，上调N-cadherin、Vimentin和其他干细胞相关标志物（CD 133、Oct 4、c-Myc）的表达。当给予ZA共处理时，这种作用被抑制，因为ZA抑制了M2样TAM的极化和β-连环蛋白进入细胞核。结论：ZA通过抑制M2-like TAMs的极化和Wnt/beta-catenin通路，抑制M2-like TAMs诱导的TC细胞增殖、干性和转移，为TC的发病机制提供了新的思路，为临床治疗TC提供了新的思路。
Aims: This study aims to explore the effect and underlying mechanism of zoledronic acid (ZA) on the incidence of thyroid cancer (TC) tumorigenesis.Materials and methods: Human mononuclear cells THP-1 were differentiated into M2-like tumor associated macrophages (TAMs) by incubation with PMA followed by additional incubation of IL-4 and IL-13. TC cells TPC-1 and IHH4 were co-cultured with M2-like TAMs. Identification of M2-like TAMs markers were determined by immunohistochemistry or flow cytometry. Cell proliferation, stemness and migration/invasion ability were measured by colony, sphere formation assay and transwell assay, respectively. The expression levels of cell stemness, EMT and Wnt/beta-catenin pathway-related factors were verified by qRT-PCR, Western blotting, and immunofluorescence. A subcutaneous tumor model was established in nude mice to examine the in vivo effects of ZA.Key findings: M2-like TAMs were enriched in TC tissues, and they promoted the colony/sphere formation, accompanied with a down-regulated expression in E-cadherin and an up-regulated expression in N-cadherin, Vimentin and other stemness-associated markers (CD133, Oct4, c-Myc) in TC cells. The effects were suppressed when ZA co-treatment was given, because ZA inhibited the polarization of M2-like TAMs and beta-catenin entry into the nucleus. Moreover, in agreement with in vitro data, ZA also limited subcutaneous tumor formation and macrophage enrichment in nude mice.Significance: ZA suppressed M2-like TAMs induced TC cell proliferation, stemness and metastasis through inhibiting M2-like TAMs polarization and Wnt/beta-catenin pathway, which sheds light on the mechanisms of TC and provides avenues for the development of clinical therapy to TC.