STAT3 can be activated through paracrine signaling in breast epithelial cells.
STAT3 can be activated through paracrine signaling in breast epithelial cells.
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DOI：
10.1186/1471-2407-8-302
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发表时间：
2008-10-21
期刊：
影响因子：
3.8
通讯作者：
Lin J
中科院分区：
文献类型：
--
作者：
Lieblein JC;Ball S;Hutzen B;Sasser AK;Lin HJ;Huang TH;Hall BM;Lin J
许多癌症，包括乳腺癌，已被鉴定为信号转导子和转录激活子 3 (STAT3) 蛋白的磷酸化或活性形式水平升高。然而，肿瘤微环境是否在这种激活中发挥作用仍知之甚少。将含有来自 MDA-MB-231 和 MDA-MB-468 乳腺癌细胞以及乳腺癌相关成纤维细胞的可溶性因子的条件培养基添加到 MCF-10A 乳腺上皮细胞和 MDA-MB-453 乳腺癌细胞中。在存在或不存在中和的 IL-6 抗体或 JAK/STAT3 抑制剂 JSI-124 的情况下，通过蛋白质印迹法测定条件培养基对磷酸化 STAT3 (p-STAT3) 水平的刺激。对存在或不存在JSI-124的情况下条件培养基对MCF-10A细胞中细胞增殖的刺激进行MTT分析。通过 ELISA 分析测定 IL-6、IL-10 和 VEGF 水平。我们的结果表明，来自具有组成型活性 STAT3 的细胞系的条件培养基足以在 p-STAT3 水平不升高的各种受体中诱导 p-STAT3 水平。该信号通过 JAK/STAT3 途径发生，最早 30 分钟就会导致 STAT3 磷酸化，并持续至少 24 小时。 ELISA 分析证实 IL-6 产生水平升高与 p-STAT3 之间存在相关性。 IL-6 配体或 gp130 的中和足以阻止处理细胞中 p-STAT3 (Y705) 水平的升高。此外，MDA-MB-231条件培养基中的可溶性因子也足以刺激MCF-10A细胞产生IL-6的增加。这些结果表明，乳腺上皮细胞中的 STAT3 磷酸化可以通过来自乳腺癌细胞和乳腺癌相关成纤维细胞的可溶性因子的旁分泌信号来刺激，STAT3 磷酸化升高。 STAT3 磷酸化的诱导是通过 IL-6/JAK 途径进行的，并且似乎与细胞增殖相关。了解 IL-6 和其他可溶性因子如何通过肿瘤微环境导致 STAT3 激活将为乳腺癌和其他 p-STAT3 水平升高的癌症提供新的治疗方案。
Many cancers, including breast cancer, have been identified with increased levels of phosphorylated or the active form of Signal Transducers and Activators of Transcription 3 (STAT3) protein. However, whether the tumor microenvironment plays a role in this activation is still poorly understood. Conditioned media, which contains soluble factors from MDA-MB-231 and MDA-MB-468 breast cancer cells and breast cancer associated fibroblasts, was added to MCF-10A breast epithelial and MDA-MB-453 breast cancer cells. The stimulation of phosphorylated STAT3 (p-STAT3) levels by conditioned media was assayed by Western blot in the presence or absence of neutralized IL-6 antibody, or a JAK/STAT3 inhibitor, JSI-124. The stimulation of cell proliferation in MCF-10A cells by conditioned media in the presence or absence of JSI-124 was subjected to MTT analysis. IL-6, IL-10, and VEGF levels were determined by ELISA analysis. Our results demonstrated that conditioned media from cell lines with constitutively active STAT3 are sufficient to induce p-STAT3 levels in various recipients that do not possess elevated p-STAT3 levels. This signaling occurs through the JAK/STAT3 pathway, leading to STAT3 phosphorylation as early as 30 minutes and is persistent for at least 24 hours. ELISA analysis confirmed a correlation between elevated levels of IL-6 production and p-STAT3. Neutralization of the IL-6 ligand or gp130 was sufficient to block increased levels of p-STAT3 (Y705) in treated cells. Furthermore, soluble factors within the MDA-MB-231 conditioned media were also sufficient to stimulate an increase in IL-6 production from MCF-10A cells. These results demonstrate STAT3 phosphorylation in breast epithelial cells can be stimulated by paracrine signaling through soluble factors from both breast cancer cells and breast cancer associated fibroblasts with elevated STAT3 phosphorylation. The induction of STAT3 phosphorylation is through the IL-6/JAK pathway and appears to be associated with cell proliferation. Understanding how IL-6 and other soluble factors may lead to STAT3 activation via the tumor microenvironment will provide new therapeutic regimens for breast carcinomas and other cancers with elevated p-STAT3 levels.
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DOI：
10.1186/bcr1680
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Berishaj M;Gao SP;Ahmed S;Leslie K;Al-Ahmadie H;Gerald WL;Bornmann W;Bromberg JF
通讯作者：
Bromberg JF
影响因子：
4.4
作者：
COPELAND, NG;GILBERT, DJ;JENKINS, NA
通讯作者：
JENKINS, NA
影响因子：
56.9
作者：
Darnell, JE
通讯作者：
Darnell, JE
影响因子：
11.5
作者：
Duan, Zhenfeng;Foster, Rosemary;Seiden, Michael V.
通讯作者：
Seiden, Michael V.
影响因子：
64.5
作者：
Bromberg, JF;Wrzeszczynska, MH;Darnell, JE
通讯作者：
Darnell, JE