A miR-125b/CSF1-CX3CL1/tumor-associated macrophage recruitment axis controls testicular germ cell tumor growth
A miR-125b/CSF1-CX3CL1/tumor-associated macrophage recruitment axis controls testicular germ cell tumor growth
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miR-125b/CSF1-CX3CL1/肿瘤相关巨噬细胞招募轴控制睾丸生殖细胞肿瘤生长
DOI：
10.1038/s41419-018-1021-z
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发表时间：
2018-09-20
影响因子：
9
通讯作者：
Liu, Yi-Xun
中科院分区：
文献类型：
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作者：
Batool, Aalia;Wang, Yu-Qian;Liu, Yi-Xun
肿瘤生长受癌细胞和肿瘤微环境之间的串扰调节。最近的进展表明，肿瘤细胞中的miRNA功能障碍可以调节肿瘤微环境，从而间接决定其进展。然而，这一过程在睾丸生殖细胞肿瘤（TGCT）中知之甚少。我们在这里报道了miR-125 b在TGCT样品中通过表观遗传修饰而不是遗传改变被抑制。此外，miR-125 b过表达在两种NCCIT人胚胎癌异种移植模型中显著减轻了体内肿瘤生长，而miR-125 b在体外不刺激自主肿瘤细胞生长。值得注意的是，NCCIT胚胎癌细胞中miR-125 b的强制表达降低了肿瘤微环境中宿主肿瘤相关巨噬细胞（TAM）的丰度。通过氯甲双磷酸选择性删除宿主巨噬细胞，消除了异种移植模型中miR-125 b的抗肿瘤能力。通过RNA分析、Western印迹和荧光素酶报告基因分析，我们进一步观察到miR-125 b直接调控肿瘤细胞衍生的趋化因子CSF 1和CX 3CL 1，这两种趋化因子已知控制TAM向肿瘤部位的募集。最后，我们发现，一组miRNAs，这是在miR-125 b的调控下，可能收敛靶向NCCIT细胞中的CSF 1/CX 3CL 1使用miRNA谱。这些发现揭示了miR-125 b通过介导TGCT异种移植模型中的肿瘤-间质串扰的抗癌作用，并提高了靶向miR-125 b作为miRNA治疗剂的可能性。
Tumor growth is modulated by crosstalk between cancer cells and the tumor microenvironment. Recent advances have shown that miRNA dysfunction in tumor cells can modulate the tumor microenvironment to indirectly determine their progression. However, this process is poorly understood in testicular germ cell tumors (TGCTs). We reported here that miR-125b was repressed in TGCT samples by epigenetic modifications rather than genetic alternations. Furthermore, miR-125b overexpression significantly alleviated the tumor growth in two NCCIT human embryonic carcinoma xenograft models in vivo, whereas miR-125b did not stimulate autonomous tumor cell growth in vitro. Notably, forced expression of miR-125b in NCCIT embryonic carcinoma cells decreased the abundance of host tumor-associated macrophages (TAMs) within tumor microenvironment. Selective deletion of host macrophages by clodronate abolished the anti-tumoral ability of miR-125b in xenograft models. By RNA profiling, Western blot and luciferase reporter assay, we further observed that miR-125b directly regulated tumor cell-derived chemokine CSF1 and CX3CL1, which are known to control the recruitment of TAMs to tumor sites. Lastly, we found that one set of miRNAs, which are under the regulation of miR-125b, might convergently target CSF1/CX3CL1 in NCCIT cells using miRNA profiling. These findings uncover the anticancer effect of miR-125b via mediating tumor-stroma crosstalk in xenograft models of TGCTs and raise the possibility of targeting miR-125b as miRNA therapeutics.