Tumor-derived miR-130b-3p induces cancer-associated fibroblast activation by targeting SPIN90 in luminal A breast cancer.
Tumor-derived miR-130b-3p induces cancer-associated fibroblast activation by targeting SPIN90 in luminal A breast cancer.
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DOI：
10.1038/s41389-022-00422-6
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发表时间：
2022-08-10
期刊：
影响因子：
6.2
通讯作者：
Song, Woo Keun
中科院分区：
文献类型：
--
作者：
Ahn, Suyeon;Kwon, Ahreum;Huh, Yun Hyun;Rhee, Sangmyung;Song, Woo Keun
肿瘤微环境（TME）中的癌症相关成纤维细胞（CAF）与癌细胞密切相互作用，促进肿瘤的发展。据报道，CAF 中 SPIN90 的下调可促进乳腺癌进展，但其潜在机制尚未阐明。在这里，我们证明 miR-130b-3p 直接下调基质成纤维细胞中的 SPIN90，导致其分化为 CAF。由于本研究显示CAF中SPIN90的减少在雌激素受体（ER）阳性乳腺癌肿瘤中更为明显，因此通过对ER阳性乳腺癌患者数据的生物信息学分析选择了miR-130b-3p。成纤维细胞中 miR-130b-3p 的异位表达加速了它们向 CAF 的分化，从而促进癌细胞运动；这与 SPIN90 下调有关。我们还发现miR-130b-3p在管腔A型癌细胞中产生，并通过癌细胞的外泌体分泌后激活成纤维细胞。最后，在 SPIN90 下调的 Luminal A 乳腺癌患者和 MCF7 细胞异种移植模型小鼠的肿瘤基质中，miR-130b-3p 增加。我们的数据表明 miR-130b-3p 是下调乳腺 CAF 中 SPIN90 的关键调节剂。肿瘤基质中 miR-130b-3p 和 SPIN90 之间的负相关表明 miR-130b-3p/SPIN90 轴对于乳腺癌进展期间的 CAF 激活具有临床意义。
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) interact closely with cancer cells to promote tumor development. Downregulation of SPIN90 in CAFs has been reported to facilitate breast cancer progression, but the underlying mechanism has not been elucidated. Here, we demonstrate that miR-130b-3p directly downregulates SPIN90 in stromal fibroblasts, leading to their differentiation into CAFs. As the decrease of SPIN90 in CAFs was shown to be more prominent in estrogen receptor (ER)-positive breast tumors in this study, miR-130b-3p was selected by bioinformatics analysis of data from patients with ER-positive breast cancer. Ectopic expression of miR-130b-3p in fibroblasts accelerated their differentiation to CAFs that promote cancer cell motility; this was associated with SPIN90 downregulation. We also found that miR-130b-3p was generated in luminal A-type cancer cells and activated fibroblasts after being secreted via exosomes from cancer cells. Finally, miR-130b-3p increased in SPIN90-downregulated tumor stroma of luminal A breast cancer patients and MCF7 cell-xenograft model mice. Our data demonstrate that miR-130b-3p is a key modulator that downregulates SPIN90 in breast CAFs. The inverse correlation between miR-130b-3p and SPIN90 in tumor stroma suggests that the miR-130b-3p/SPIN90 axis is clinically significant for CAF activation during breast cancer progression.
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影响因子：
5.6
作者：
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通讯作者：
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