Yao Xiaoli, Liu Hua, Zhang Xinghua, Zhang Liang, Li Xiang, Wang Changhua, Sun Shengrong
Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
Department of Clinical Pathology, The First People's Hospital of Lianyungang, Lianyungang, 222000, Jiangsu Province, China; Department of Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, Hubei Province, China.
PLoS One. 2015 May 14;10(5):e0125634. doi: 10.1371/journal.pone.0125634. eCollection 2015.
High levels of cell surface glucose regulated protein 78 (sGRP78) have been implicated in cancer growth, survival, metastasis, and chemotherapy resistance. However, the underlying mechanism remains largely unknown. Here we report that the level of sGRP78 expression in human breast tumors gradually increases during cancer progression. Overexpression of GRP78 significantly enhanced its membrane distribution in human MCF-7 breast cancer cells, but had no effect on endoplasmic reticulum (ER) stress. High levels of sGRP78 facilitated cell proliferation and migration, as well as suppressed cell apoptosis. Neutralization of sGRP78 by a specific antibody against GRP78 alleviated sGRP78-induced cell growth and migration. Importantly, high phosphorylation levels of the signal transducer and activator of transcription 3 (STAT3) were found in human breast tumors that express sGRP78 and MCF-7 cells infected with adenovirus encoding human GRP78. Pretreatment with a GRP78 antibody suppressed STAT3 phosphorylation. Furthermore, genetic and pharmacological inhibition of STAT3 reversed the impacts of GRP78 on cell proliferation, apoptosis, and migration. These findings indicate that STAT3 mediates sGRP78-promoted breast cancer cell growth and migration.
高水平的细胞表面葡萄糖调节蛋白78（sGRP78）与癌症的生长、存活、转移及化疗耐药性有关。然而，其潜在机制仍 largely 未知。在此我们报告，在癌症进展过程中，人乳腺肿瘤中 sGRP78 的表达水平逐渐升高。GRP78 的过表达显著增强了其在人MCF-7乳腺癌细胞中的膜分布，但对内质网（ER）应激无影响。高水平的 sGRP78 促进细胞增殖和迁移，并抑制细胞凋亡。用针对 GRP78 的特异性抗体中和 sGRP78 可减轻 sGRP78 诱导的细胞生长和迁移。重要的是，在表达 sGRP78 的人乳腺肿瘤及感染编码人 GRP78 的腺病毒的 MCF-7 细胞中发现信号转导和转录激活因子 3（STAT3）的高磷酸化水平。用 GRP78 抗体预处理可抑制 STAT3 磷酸化。此外，对 STAT3 的基因和药理学抑制逆转了 GRP78 对细胞增殖、凋亡和迁移的影响。这些发现表明 STAT3 介导 sGRP78 促进的乳腺癌细胞生长和迁移。
