Exosomes Derived from Pancreatic Cancer Cells Induce Osteoclast Differentiation Through the miR125a-5p/TNFRSF1B Pathway.
Exosomes Derived from Pancreatic Cancer Cells Induce Osteoclast Differentiation Through the miR125a-5p/TNFRSF1B Pathway.
复制标题
胰腺癌细胞来源的外泌体通过 MiR125a-5p/TNFRSF1B 途径诱导破骨细胞分化
DOI：
10.2147/ott.s282319
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发表时间：
2021
影响因子：
4
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Zhou Y;Zhu Y;Dong X;Cao G;Li Y;Fan Y;Chen Q;Cai H;Wu Y
在美国，胰腺癌(PC)被认为是癌症相关死亡的第四大原因，患者通常患有严重的营养缺乏、肌肉萎缩和骨质丢失。在我们之前的研究中，我们已经发现PC衍生的外切体可能会在骨骼肌细胞中引发胰岛素抵抗。然而，外切体在PC相关骨丢失中的作用仍不清楚。在异种小鼠原位移植模型中，观察PC来源的外切体对破骨细胞分化和股骨结构的影响。检测miRNA的表达谱，并进行双荧光素酶实验以确定miRNA的直接靶标。我们的数据显示，PC来源的Exosome显著诱导破骨细胞分化，并增加NFAT2、TRAP、CTSK和MMP-9的表达。骨质疏松模型大鼠股骨骨体积分数和骨小梁厚度明显降低。基因芯片分析和荧光素酶报告分析表明，这一过程至少部分是由miR-125A-5P/TNFRSF1B信号通路介导的。根据这一结果，从PC衍生的外切体对骨骼退化的影响有了新的见解，并解释了PC与癌症相关的骨丢失的相关性。
Pancreatic cancer (PC) was regarded as the 4th principal cause of cancer-related fatalities in the United States and patients usually suffered from severe nutrition deficiency, muscle wasting, as well as bone loss. In our previous research, we have found that PC-derived exosomes potentially initiate insulin resistance in skeletal muscle cells. However, the role of exosomes in the PC-related bone loss remains unknown. The effect of PC-derived exosomes on the osteoclast differentiation and femoral bone structure in the orthotopic xenograft mouse model were investigated. MiRNA expression profiles were detected and a dual luciferase experiment was conducted to identify the direct target of miRNA. Our data showed that PC-derived exosomes significantly induced osteoclast differentiation and increased expression of NFAT2, TRAP, CTSK and MMP-9. The bone volume fraction and trabecular thickness of femur significantly reduced in osteoporotic model. Microarray analyses and luciferase reporter assay showed that the process was, at least partially, mediated by the miR-125a-5p/TNFRSF1B signaling pathways. According to the results, novel insights have been claimed the effect of exosomes derived from PC on bone deterioration and explained correlation between PC and cancer-related bone loss.