β2-微球蛋白通过与 HER2 过表达乳腺癌中的 HFE 直接相互作用，通过 ERK 信号通路诱导肿瘤细胞凋亡。

β2-microglobulin induced apoptosis of tumor cells via the ERK signaling pathway by directly interacting with HFE in HER2-overexpressing breast cancer.

机构信息

Department of Medicine Biotechnology, Gansu Provincial Academic Institute for Medical Research, 2 East Xiaoxihu Street, Lanzhou, China.

Bioscience College, Lanzhou University, Lanzhou, China.

出版信息

BMC Cancer. 2024 Aug 12;24(1):991. doi: 10.1186/s12885-024-12757-x.

DOI:10.1186/s12885-024-12757-x

PMID:39128984

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11318297/

Abstract

BACKGROUND

Our previous study demonstrated that β2-microglobulin (β2M) promoted ER/HER2 breast cancer survival via the SGK1/Bcl-2 signaling pathway. However, the role of β2M has not been investigated in ER/HER2 breast cancer. Here, we aimed to determine the role of β2M in ER/HER2 breast cancer.

METHODS

The interaction between β2M and HFE was confirmed by co-immunoprecipitation, mass spectrometry, yeast two-hybrid screening, and His pull-down. The knockdown and overexpression of β2M or HFE were performed in MDA-MB-453 cells, and ERK signaling pathway was subsequently analyzed via western blotting. Apoptotic cells were detected using flow cytometer. β2M, HFE, and p-ERK1/2 were examined in tumor and paired adjacent tissues via immunohistochemistry.

RESULTS

HFE was found to be an interacting protein of β2M in ER/HER2 breast cancer cells MDA-MB-453 by co-immunoprecipitation and mass spectrometry. A yeast two-hybrid system and His-pull down experiments verified that β2M directly interacted with HFE. β2M and HFE as a complex were mainly located in the cytoplasm, with some on the cytomembrane of MDA-MB-453 cells. In addition to breast cancer cells BT474, endogenous β2M directly interacted with HFE in breast cancer cells MDA-MB-453, MDA-MB-231, and MCF-7. β2M activated the ERK signaling pathway by interacting with HFE and induced apoptosis of MDA-MB-453 cells. The expression of HFE and p-ERK1/2 showed significantly high levels in HER2-overexpressing breast cancer tumor tissue compared with adjacent normal tissue, consistent with the results obtained from the cell experiments.

CONCLUSIONS

β2M induced apoptosis of tumor cells via activation of the ERK signal pathway by directly interacting with HFE in HER2-overexpressing breast cancer.

摘要

背景

我们之前的研究表明β2-微球蛋白（β2M）通过 SGK1/Bcl-2 信号通路促进 ER/HER2 乳腺癌的存活。然而，β2M 在 ER/HER2 乳腺癌中的作用尚未被研究。在这里，我们旨在确定β2M 在 ER/HER2 乳腺癌中的作用。

方法

通过免疫共沉淀、质谱、酵母双杂交筛选和 His 下拉验证β2M 与 HFE 的相互作用。在 MDA-MB-453 细胞中敲低和过表达β2M 或 HFE，然后通过 Western blot 分析 ERK 信号通路。使用流式细胞仪检测凋亡细胞。通过免疫组化检测肿瘤和配对相邻组织中的β2M、HFE 和 p-ERK1/2。

结果

通过免疫共沉淀和质谱发现 HFE 是 ER/HER2 乳腺癌细胞 MDA-MB-453 中β2M 的相互作用蛋白。酵母双杂交系统和 His 下拉实验验证了β2M 与 HFE 直接相互作用。β2M 和 HFE 作为复合物主要位于细胞质中，部分位于 MDA-MB-453 细胞的质膜上。除了乳腺癌细胞 BT474 之外，内源性β2M 在乳腺癌细胞 MDA-MB-453、MDA-MB-231 和 MCF-7 中也直接与 HFE 相互作用。β2M 通过与 HFE 相互作用激活 ERK 信号通路，诱导 MDA-MB-453 细胞凋亡。与细胞实验结果一致，HER2 过表达乳腺癌肿瘤组织中 HFE 和 p-ERK1/2 的表达明显高于相邻正常组织。