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条件性敲低骨桥蛋白抑制乳腺癌骨转移。

Conditional Knockdown of Osteopontin Inhibits Breast Cancer Skeletal Metastasis.

机构信息

German Cancer Research Center (DKFZ), Toxicology and Chemotherapy Unit, 69120 Heidelberg, Germany.

Central Institute of Mental Health, Department of Molecular Biology, 68159 Mannheim, Germany.

出版信息

Int J Mol Sci. 2019 Oct 4;20(19):4918. doi: 10.3390/ijms20194918.

DOI:10.3390/ijms20194918
PMID:31590218
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6801824/
Abstract

High osteopontin (OPN) expression is linked to breast cancer bone metastasis. In this study we modulated osteopontin levels conditionally and investigated any related antineoplastic effects. Therefore, we established cell clones from human breast cancer MDA-MB-231 cells, in which the expression of OPN is regulated by the Tet-Off tet-off system. These cells, which conditionally express a specific miRNA targeting OPN, were used for in vitro studies as well as for a bone metastasis model in nude rats. Changes in whole-genome expression elicited by conditional OPN knockdown and vesicle formation were also analyzed. The alkylphosphocholine erufosine was used for combination therapy. Conditional OPN knockdown caused mild anti-proliferative, but more intensive anti-migratory and anti clonogenic effects, as well as partial and complete remissions of soft tissue and osteolytic lesions. These effects were associated with specific gene and protein expression modulations following miRNA-mediated OPN knockdown. Furthermore, high levels of OPN were detected in vesicles derived from rats harboring breast cancer skeletal metastases. Finally, the combination of OPN inhibition and erufosine treatment caused an additive reduction of OPN levels in the investigated breast cancer cells. Thus, knockdown of OPN alone or in combination with erufosine is a promising strategy in breast cancer skeletal metastasis treatment.

摘要

骨桥蛋白（OPN）高表达与乳腺癌骨转移有关。在本研究中，我们条件性地调节骨桥蛋白水平，研究任何相关的抗肿瘤作用。因此，我们从人乳腺癌 MDA-MB-231 细胞中建立了细胞克隆，其中 OPN 的表达受 Tet-Off tet-off 系统调控。这些细胞特异性表达针对 OPN 的特定 miRNA，可以用于体外研究以及裸鼠骨转移模型。还分析了条件性 OPN 敲低和囊泡形成引起的全基因组表达变化。烷基膦胆碱依鲁替尼用于联合治疗。条件性 OPN 敲低导致轻微的抗增殖作用，但更强烈的抗迁移和抗集落形成作用，以及软组织和溶骨性病变的部分和完全缓解。这些作用与 miRNA 介导的 OPN 敲低后特定基因和蛋白表达的调节有关。此外，在患有乳腺癌骨转移的大鼠来源的囊泡中检测到高水平的 OPN。最后，OPN 抑制与依鲁替尼联合治疗导致所研究的乳腺癌细胞中 OPN 水平的相加降低。因此，单独或联合依鲁替尼抑制 OPN 是治疗乳腺癌骨转移的一种有前途的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a06f/6801824/909e553321bd/ijms-20-04918-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a06f/6801824/a93f759ceffe/ijms-20-04918-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a06f/6801824/e20483dd3234/ijms-20-04918-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a06f/6801824/7e74b09ca0d1/ijms-20-04918-g003.jpg
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