cyclic-guanosine-monophosphate-adenosine-monophosphate and Breast-Neoplasms

To investigate the effects of cyclic GMP-AMP synthase (cGAS) on the proliferation, migration and epithelial to mesenchymal transition (EMT) of breast cancer cells.. The cGAS lentiviral vector and control fluorescence vector were transfected into breast cancer MCF7 cells and were divided into negative group (NC) and MCF7-cGAS group. The effect of cGAS on proliferation in the MCF7 cells was detected by MTT. The effect of cGAS on cell migration was detected by Transwell assay. The expressions of EMT related proteins were analyzed by Western blot.. After over-expressed with cGAS, the proliferation and migration of MCF7 cells were increased (. The over-expression of cGAS increased the proliferation and migration of breast cancer cells and induced EMT in breast cancer cells.. 目的: 探讨环状GMP-AMP合成酶(cGAS)高表达对乳腺癌MCF7细胞发生上皮间质转化(EMT)的影响。方法: 构建稳定高表达cGAS的慢病毒载体并转染MCF7细胞;转染后细胞分别培养12 h,24 h,48 h,72 h,每组实验重复三次,采用MTT检测cGAS对MCF7细胞增殖的影响; transwell法检测高表达cGAS对MCF7细胞迁移能力的影响;蛋白免疫印迹(Western blot)法分析EMT相关蛋白E-cadherin和N-cadherin的表达情况。结果: 与对照组比较,cGAS上调后MCF7细胞增殖能力显著增强(

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Female; Humans; Nucleotides, Cyclic; Nucleotidyltransferases

Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. We show that human and mouse breast and lung cancer cells express protocadherin 7 (PCDH7), which promotes the assembly of carcinoma-astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells use these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines such as interferon-α (IFNα) and tumour necrosis factor (TNF). As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, thereby supporting tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle that these drugs could be used to treat established brain metastasis.

Topics: Animals; Astrocytes; Benzamides; Benzopyrans; Brain Neoplasms; Breast Neoplasms; Cadherins; Cell Line, Tumor; Coculture Techniques; Connexin 43; Drug Resistance, Neoplasm; Female; Gap Junctions; Humans; Immunity, Innate; Interferon-alpha; Lung Neoplasms; Meclofenamic Acid; Membrane Proteins; Mice; NF-kappa B; Nucleotides, Cyclic; Paracrine Communication; Protocadherins; STAT1 Transcription Factor; Tumor Necrosis Factors; Xenograft Model Antitumor Assays