β2-微球蛋白在具有 HER2 的 ER 和 ER 乳腺癌之间具有不同的调节分子机制。
β2-microglobulin has a different regulatory molecular mechanism between ER and ER breast cancer with HER2.
机构信息
Department of Medicine Biotechnology, Medicine and Science Research Institute of Gansu Province, Lanzhou, China.
Department of Breast Surgery, Tumor Hospital of Gansu Province, Lanzhou, China.
出版信息
BMC Cancer. 2019 Mar 12;19(1):223. doi: 10.1186/s12885-019-5410-1.
BACKGROUND
Previous studies have demonstrated that β2-microglobulin (β2M) promotes the growth and survival of a variety of cancer cells and has different regulatory effects on the expression of Bcl-2 and HER2 in HER2 breast cancer cells. However, β2M-mediated signaling in ER and ER breast cancer with HER2 remains unclear.
METHODS
β2M expression vector and siRNA were transfected into two types of HER2 breast cancer cells, and the possible relevant signaling molecules were subsequently analyzed by real-time PCR and western blotting. These signaling molecules were also analyzed by real-time PCR and immunohistochemistry (IHC) in two types of HER2 breast cancer tissues, and the associations between β2M and these signaling molecules were assessed using Spearman's correlation analysis.
RESULTS
β2M silencing downregulated p-SGK1/SGK1 levels and Bcl-2 expression, and β2M overexpression downregulated p-CREB/CREB and significantly upregulated p-SGK1/SGK1 levels and Bcl-2 expression, and both resulting processes did not affect HER2, HIF-1α, VEGF, and ERK signaling in ER breast cancer cells with HER2. β2M silencing upregulated p-CREB/CREB and VEGF protein and significantly downregulated p-ERK/ERK levels, and β2M overexpression downregulated p-CREB/CREB and VEGF, significantly upregulated p-ERK/ERK levels, and both resulting processes did not affect HIF-1α and SGK1 signaling in ER breast cancer cells with HER2. β2M expression was positively correlated with p-CREB, p-SGK1, and Bcl-2 expression and had no correlation with HIF-1α, VEGF, and p-ERK1/2, whereas p-SGK1 exhibited a significantly positive correlation with Bcl-2 expression in cancer tissues of patients with luminal A breast cancer, which coincide with the results obtained from the same molecular types of breast cancer cells except CREB signaling. However, β2M expression did not show a significant correlation with HIF-1α, p-CREB, VEGF, p-SGK1, p-ERK1/2, and Bcl-2 expression in cancer tissues of patients with basal-like breast cancer, which was discordant with the results obtained from the same molecular types of breast cancer cells.
CONCLUSIONS
β2M has a different molecular regulatory mechanism between ER and ER breast cancer with HER2, and it may promote tumor survival through the SGK1/Bcl-2 signaling pathway in ER breast cancer with HER2 and has no regulatory effects on ER breast cancer with HER2.
背景
先前的研究表明，β2-微球蛋白（β2M）促进多种癌细胞的生长和存活，并对 HER2 乳腺癌细胞中 Bcl-2 和 HER2 的表达具有不同的调节作用。然而，β2M 介导的信号转导在 ER 和 ER 阳性乳腺癌中的作用仍不清楚。
方法
将β2M 表达载体和 siRNA 转染到两种 HER2 乳腺癌细胞中，然后通过实时 PCR 和 Western blot 分析可能的相关信号分子。还通过实时 PCR 和免疫组织化学（IHC）分析两种 HER2 乳腺癌组织中的这些信号分子，并使用 Spearman 相关分析评估β2M 与这些信号分子之间的相关性。
结果
β2M 沉默下调 p-SGK1/SGK1 水平和 Bcl-2 表达，而β2M 过表达下调 p-CREB/CREB，并显著上调 p-SGK1/SGK1 水平和 Bcl-2 表达，这两个过程均不影响 ER 阳性乳腺癌细胞中的 HER2、HIF-1α、VEGF 和 ERK 信号。β2M 沉默上调 p-CREB/CREB 和 VEGF 蛋白，并显著下调 p-ERK/ERK 水平，而β2M 过表达下调 p-CREB/CREB 和 VEGF，显著上调 p-ERK/ERK 水平，这两个过程均不影响 ER 阳性乳腺癌细胞中的 HIF-1α 和 SGK1 信号。β2M 表达与 p-CREB、p-SGK1 和 Bcl-2 表达呈正相关，与 HIF-1α、VEGF 和 p-ERK1/2 无相关性，而 p-SGK1 与 luminal A 乳腺癌患者的癌组织中 Bcl-2 表达呈显著正相关，与除 CREB 信号外的相同分子类型乳腺癌细胞的结果一致。然而，β2M 表达与基底样乳腺癌患者的癌组织中 HIF-1α、p-CREB、VEGF、p-SGK1、p-ERK1/2 和 Bcl-2 表达无显著相关性，与相同分子类型乳腺癌细胞的结果不一致。
结论
β2M 在 ER 和 ER 阳性乳腺癌中的分子调控机制不同，它可能通过 SGK1/Bcl-2 信号通路促进 ER 阳性乳腺癌中的肿瘤存活，而对 ER 阳性乳腺癌无调节作用。
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