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单克隆抗体 NJ001 通过与 FOXP1 结合位点直接调节 TIMP-3 启动子活性来抑制肺腺癌的侵袭性。

MAb NJ001 inhibits lung adenocarcinoma invasiveness by directly regulating TIMP-3 promoter activity via FOXP1 binding sites.

机构信息

Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

National Key Clinical Department of Laboratory Medicine, Nanjing, China.

出版信息

Thorac Cancer. 2020 Sep;11(9):2630-2638. doi: 10.1111/1759-7714.13593. Epub 2020 Aug 3.

DOI:10.1111/1759-7714.13593
PMID:32744429
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7471035/
Abstract

BACKGROUND

Previously, we developed a monoclonal antibody (mAb) NJ001 that binds to the antigen SP70 in human non-small cell lung cancer (NSCLC) cells and showed it could inhibit lung adenocarcinoma (AD) growth. Here, we investigated the effect and mechanisms of NJ001 in lung AD metastasis.

METHODS

Human lung AD cells (SPC-A1 and A549) were treated with different concentrations of mAb NJ001, and the effects of NJ001 on cell migration and invasive activity were investigated using wound-healing and Matrigel assays, respectively. The molecular mechanism of this inhibition was explored by microarrays, qRT-PCR, western blot, luciferase assays and electrophoretic mobility shift assays (EMSA).

RESULTS

MAb NJ001 markedly suppressed lung AD cell migration; and the invasiveness of SPC-A1 and A549 cells treated with mAb NJ001 was diminished by 65%. Tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) was highly expressed in SPC-A1 cells treated with mAb NJ001, whereas knockdown of TIMP-3 by shRNA significantly increased SPC-A1 and A549 invasiveness. MAb NJ001 affects lung AD by inhibiting TIMP-3 through direct transcriptional regulation of FOXP1 binding sites in the TIMP-3 promoter region, as shown in luciferase assays and EMSA.

CONCLUSIONS

MAb NJ001 inhibits invasiveness and metastasis in lung AD through the FOXP1 binding sites in the TIMP-3 promoter region. It may have clinical applications in preventing and treating metastatic lung AD.

摘要

背景

此前，我们开发了一种单克隆抗体（mAb）NJ001，它能与人类非小细胞肺癌（NSCLC）细胞中的抗原 SP70 结合，并能抑制肺腺癌（AD）生长。在这里，我们研究了 NJ001 在肺 AD 转移中的作用和机制。

方法

用不同浓度的 mAb NJ001 处理人肺 AD 细胞（SPC-A1 和 A549），分别用划痕实验和 Matrigel 实验检测 NJ001 对细胞迁移和侵袭活性的影响。通过微阵列、qRT-PCR、western blot、荧光素酶实验和电泳迁移率变动实验（EMSA）探讨这种抑制的分子机制。

结果

mAb NJ001 显著抑制肺 AD 细胞迁移；用 mAb NJ001 处理的 SPC-A1 和 A549 细胞的侵袭性降低了 65%。在 mAb NJ001 处理的 SPC-A1 细胞中，基质金属蛋白酶组织抑制剂 3（TIMP-3）高度表达，而通过 shRNA 敲低 TIMP-3 则显著增加了 SPC-A1 和 A549 的侵袭性。通过荧光素酶实验和 EMSA 表明，mAb NJ001 通过直接转录调控 TIMP-3 启动子区域中的 FOXP1 结合位点，影响肺 AD，从而抑制 TIMP-3。

结论

mAb NJ001 通过 TIMP-3 启动子区域中的 FOXP1 结合位点抑制肺 AD 的侵袭和转移。它可能在预防和治疗转移性肺 AD 方面具有临床应用价值。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6d/7471035/ed697f708ab9/TCA-11-2630-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6d/7471035/debb077cf292/TCA-11-2630-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6d/7471035/47681c15619c/TCA-11-2630-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6d/7471035/34cfa8c014bd/TCA-11-2630-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6d/7471035/eeeafb27e4d2/TCA-11-2630-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6d/7471035/ed697f708ab9/TCA-11-2630-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6d/7471035/debb077cf292/TCA-11-2630-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6d/7471035/47681c15619c/TCA-11-2630-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6d/7471035/34cfa8c014bd/TCA-11-2630-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6d/7471035/eeeafb27e4d2/TCA-11-2630-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6d/7471035/ed697f708ab9/TCA-11-2630-g005.jpg

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