Microenvironment-induced TIMP2 loss by cancer-secreted exosomal miR-4443 promotes liver metastasis of breast cancer
Microenvironment-induced TIMP2 loss by cancer-secreted exosomal miR-4443 promotes liver metastasis of breast cancer
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DOI：
10.1002/jcp.29507
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发表时间：
2020-01-22
影响因子：
5.6
通讯作者：
Feng, Jifeng
中科院分区：
文献类型：
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作者：
Wang, Jinyan;Zhang, Qian;Feng, Jifeng
我们的目的是研究外泌体miR-4443在乳腺癌（BCa）转移中的作用。采用体外伤口愈合实验和transwell侵袭实验观察miR-4443对BCa细胞的影响。进行动物实验以证实其体内作用。miR-4443通过下调金属蛋白酶组织抑制因子2（TIMP 2）和上调基质金属蛋白酶（MMPs）促进BCa细胞的转移。高侵袭性BCa细胞在细胞和外来体中具有更高的miR-4443表达。来源于高度侵袭性BCa细胞的外泌体主要聚集在原发肿瘤和肝脏中。在体内，miR-4443在非侵袭性BCa细胞中的过表达诱导肝转移，伴随着原发性肿瘤和肝脏中TIMP 2的下调和MMP-2的上调。当我们用miR-4443抑制剂武装MCF-10A外泌体来治疗携带高miR-4443肿瘤的小鼠时，随着TIMP 2上调和MMP 2下调，外泌体在原发性肿瘤和肝脏中积聚，并且转移被抑制。高度侵袭性的BCa细胞通过将外泌体miR-4443递送至原发肿瘤的基质细胞并损害TIMP 2从而激活MMP来破坏针对转移的天然屏障;循环外泌体miR-4443可能通过类似的机制促进BCa细胞在未来的转移位点中停留。
We aimed to investigate the role of exosomal miR-4443 in metastasis of breast cancer (BCa). In vitro wound-healing assay and transwell invasion assay were used to investigate effect of miR-4443 on BCa cells. Animal experiments were performed to confirm its effects in vivo. miR-4443 promotes the metastasis of BCa cells through downregulating tissue inhibitors of metalloproteinase 2 (TIMP2) and upregulating matrix metalloproteinases (MMPs). Highly invasive BCa cells have a higher expression of miR-4443 in both cells and exosomes. The exosomes derived from highly invasive BCa cells mainly gather in the primary tumor and liver. In vivo, overexpression of miR-4443 in noninvasive BCa cells induces liver metastasis, accompanied with downregulated TIMP2, and upregulated MMP-2 in both the primary tumor and liver. When we armed MCF-10A exosomes with miR-4443 inhibitors to treat mice bearing high-miR-4443 tumors, exosomes accumulated in the primary tumor, and liver following the upregulation of TIMP2 and downregulation of MMP2, and the metastasis was inhibited. Highly invasive BCa cells destroy natural barriers against metastasis by delivering exosomal miR-4443 to stromal cells of the primary tumor and impairing TIMP2, consequently activating MMP; circulating exosomal miR-4443 might promote BCa cells lodging in future metastatic sites through the similar mechanisms.