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单核细胞趋化蛋白-1 通过 c-Raf/MAPK/AP-1 通路和 MMP-9 产生促进骨肉瘤中癌细胞迁移。

Monocyte Chemoattractant Protein-1 promotes cancer cell migration via c-Raf/MAPK/AP-1 pathway and MMP-9 production in osteosarcoma.

机构信息

School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei, 110, Taiwan.

Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 40447, Taiwan.

出版信息

J Exp Clin Cancer Res. 2020 Nov 23;39(1):254. doi: 10.1186/s13046-020-01756-y.

DOI:10.1186/s13046-020-01756-y
PMID:33228783
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7684958/
Abstract

BACKGROUND

Osteosarcoma is generally reported among younger individuals and has a very poor prognosis, particularly for the development of metastasis. However, more effective metastatic biomarkers and therapeutic methods are absent. Monocyte chemoattractant protein-1 (MCP-1) is involved in cancer progression and inflammatory recruitment. Although previous studies have reported higher serum MCP-1 levels in patients with osteosarcoma, the role of MCP-1 in osteosarcoma progression remains to be addressed.

METHODS

The osteosarcoma cell migratory ability was assessed by transwell migration assay. The MCP-1 and MMP-9 expression levels were analyzed by Western blot and qPCR. The signal activation was conducted by Western blot. The in vivo mouse experiment and tumor tissue array were performed to confirm our findings in vitro.

RESULTS

The present study demonstrates that MCP-1 regulates cell mobility through matrix metalloproteinase (MMP)-9 expression in osteosarcoma cells. Moreover, MCP-1 promotes MMP-9 expression, cell migration, and cell invasion by mediating CCR2, c-Raf, MAPK, and AP-1 signal transduction. Using MCP-1 knockdown stable cell lines, we found that MCP-1 knockdown reduces MMP-9 expression and cell mobility. Finally, we found high MCP-1 expression levels in osteosarcoma specimens.

CONCLUSIONS

Our results provide prognostic value of MCP-1 in osteosarcoma by promoting MMP-9 expression.

摘要

背景

骨肉瘤通常发生于年轻人，预后极差，尤其是易发生转移。然而，目前缺乏更有效的转移性生物标志物和治疗方法。单核细胞趋化蛋白-1（MCP-1）参与癌症进展和炎症募集。尽管先前的研究报告称骨肉瘤患者的血清 MCP-1 水平较高，但 MCP-1 在骨肉瘤进展中的作用仍有待解决。

方法

通过 Transwell 迁移实验评估骨肉瘤细胞的迁移能力。通过 Western blot 和 qPCR 分析 MCP-1 和 MMP-9 的表达水平。通过 Western blot 进行信号激活。进行体内小鼠实验和肿瘤组织阵列以验证我们在体外的发现。

结果

本研究表明 MCP-1 通过基质金属蛋白酶（MMP）-9 表达调节骨肉瘤细胞的细胞迁移能力。此外，MCP-1 通过介导 CCR2、c-Raf、MAPK 和 AP-1 信号转导促进 MMP-9 表达、细胞迁移和细胞侵袭。使用 MCP-1 敲低稳定细胞系，我们发现 MCP-1 敲低可降低 MMP-9 表达和细胞迁移能力。最后，我们发现骨肉瘤标本中存在高 MCP-1 表达水平。

结论

我们的研究结果通过促进 MMP-9 表达为骨肉瘤提供了 MCP-1 的预后价值。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fcd/7684958/f388447aac4d/13046_2020_1756_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fcd/7684958/75f45e521c1b/13046_2020_1756_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fcd/7684958/a5dc3895c5dd/13046_2020_1756_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fcd/7684958/44fa4ce1cfc1/13046_2020_1756_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fcd/7684958/eb570a71c679/13046_2020_1756_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fcd/7684958/39c18ce8dc37/13046_2020_1756_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fcd/7684958/d8033fde3c2d/13046_2020_1756_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fcd/7684958/f388447aac4d/13046_2020_1756_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fcd/7684958/75f45e521c1b/13046_2020_1756_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fcd/7684958/a5dc3895c5dd/13046_2020_1756_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fcd/7684958/44fa4ce1cfc1/13046_2020_1756_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fcd/7684958/eb570a71c679/13046_2020_1756_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fcd/7684958/39c18ce8dc37/13046_2020_1756_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fcd/7684958/d8033fde3c2d/13046_2020_1756_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fcd/7684958/f388447aac4d/13046_2020_1756_Fig7_HTML.jpg

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