Cell Surface GRP78 Accelerated Breast Cancer Cell Proliferation and Migration by Activating STAT3.

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.

细胞表面葡萄糖调节蛋白78（sGRP78）高水平与癌症生长、存活、转移以及化疗耐药性有关。然而，其潜在机制在很大程度上仍不明确。在此我们报道，在人类乳腺肿瘤中，sGRP78的表达水平在癌症进展过程中逐渐升高。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）应激没有影响。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可缓解sGRP78诱导的细胞生长和迁移。重要的是，在表达sGRP78的人类乳腺肿瘤以及感染了编码人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进行基因和药物抑制可逆转GRP78对细胞增殖、凋亡和迁移的影响。这些发现表明STAT3介导了sGRP78促进的乳腺癌细胞生长和迁移。