MicroRNA-222 reprogrammed cancer-associated fibroblasts enhance growth and metastasis of breast cancer
MicroRNA-222 reprogrammed cancer-associated fibroblasts enhance growth and metastasis of breast cancer
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DOI：
10.1038/s41416-019-0566-7
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发表时间：
2019-10-15
影响因子：
8.8
通讯作者：
Bhattacharyya, Arindam
中科院分区：
文献类型：
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作者：
Chatterjee, Annesha;Jana, Samir;Bhattacharyya, Arindam
背景技术背景：癌症相关的成纤维细胞（CAFs）是已知的影响肿瘤的行为，但控制这一机制知之甚少。方法：乳腺正常成纤维细胞（NFs）或CAFs从癌症中分离出激光显微切割或培养。转染成纤维细胞以操纵miR-222或核纤层蛋白B受体（LBR）。收集成纤维细胞条件培养基并用于处理上皮BC系MDA-MB-231和MDA-MB-157。结果：miR-222在CAFs中的表达明显高于NF。NF中的异位miR-222表达诱导CAF样表达谱，而CAF中的miR-222敲低抑制CAF表型。LBR被鉴定为直接的miR-222靶标，并且是功能相关的，因为LBR敲低表型模仿miR-222过表达，LBR过表达表型模仿miR-222敲低。MiR-222过表达或LBR敲低足以诱导NF显示出增强的迁移、侵袭和衰老的CAF特征，此外，来自这些成纤维细胞的条件培养基诱导BC细胞迁移和侵袭增加。结论：MiR-222/LBR在调控CAFs促癌作用中具有重要作用。该途径可能提供抑制CAF诱导的癌症进展的治疗机会。
BACKGROUND: Cancer-associated fibroblasts (CAFs) are known to impact on tumour behaviour, but the mechanisms controlling this are poorly understood.METHODS: Breast normal fibroblasts (NFs) or CAFs were isolated from cancers by laser microdissection or were cultured. Fibroblasts were transfected to manipulate miR-222 or Lamin B receptor (LBR). The fibroblast-conditioned medium was collected and used to treat epithelial BC lines MDA-MB-231 and MDA-MB-157. Migration, invasion, proliferation or senescence was assessed using transwell, MU or X-gal assays, respectively.RESULTS: MiR-222 was upregulated in CAFs as compared with NFs. Ectopic miR-222 expression in NFs induced CAF-like expression profiles, while miR-222 knockdown in CAFs inhibited CAF phenotypes. LBR was identified as a direct miR-222 target, and was functionally relevant since LBR knockdown phenocopied miR-222 overexpression and LBR overexpression phenocopied miR-222 knockdown. MiR-222 overexpression, or LBR knockdown, was sufficient to induce NFs to show the CAF characteristics of enhanced migration, invasion and senescence, and furthermore, the conditioned medium from these fibroblasts induced increased BC cell migration and invasion. The reverse manipulations in CAFs inhibited these behaviours in fibroblasts, and inhibited paracrine influences on BC cells.CONCLUSION: MiR-222/LBR have key roles in controlling pro-progression influences of CAFs in BC. This pathway may present therapeutic opportunities to inhibit CAF-induced cancer progression.