Tawara Ken, Scott Hannah, Emathinger Jacqueline, Wolf Cody, LaJoie Dollie, Hedeen Danielle, Bond Laura, Montgomery Paul, Jorcyk Cheryl
Boise State University, Biomolecular Sciences Program, Boise, ID, USA.
Boise State University, Department of Biological Sciences, Boise, ID, USA.
Oncotarget. 2019 Mar 12;10(21):2068-2085. doi: 10.18632/oncotarget.26699.
Chronic inflammation has been recognized as a risk factor for the development and maintenance of malignant disease. Cytokines such as interleukin-6 (IL-6), oncostatin M (OSM), and interleukin-1 beta (IL-1β) promote the development of both acute and chronic inflammation while promoting metrics of breast cancer metastasis. However, anti-IL-6 and anti-IL-1β therapeutics have not yielded significant results against solid tumors in clinical trials. Here we show that these three cytokines are interrelated in expression. Using the Curtis TCGA™ dataset, we have determined that there is a correlation between expression levels of OSM, IL-6, and IL-1β and reduced breast cancer patient survival ( = 0.6, = 2.2 x 10). Importantly, we confirm that OSM induces at least a 4-fold increase in IL-6 production from estrogen receptor-negative (ER-) breast cancer cells in a manner that is dependent on STAT3 signaling. Furthermore, OSM induces STAT3 phosphorylation and IL-1β promotes p65 phosphorylation to synergistically induce IL-6 secretion in ER- MDA-MB-231 and to a lesser extent in ER+ MCF7 human breast cancer cells. Induction may be reduced in the ER+ MCF7 cells due to a previously known suppressive interaction between ER and STAT3. Interestingly, we show in MCF7 cells that ER's interaction with STAT3 is reduced by 50% through both OSM and IL-1β treatment, suggesting a role for ER in mitigating STAT3-mediated inflammatory cascades. Here, we provide a rationale for a breast cancer treatment regime that simultaneously suppresses multiple targets, as these cytokines possess many overlapping functions that increase metastasis and worsen patient survival.
慢性炎症已被公认为是恶性疾病发生和维持的一个风险因素。白细胞介素-6（IL-6）、抑瘤素M（OSM）和白细胞介素-1β（IL-1β）等细胞因子在促进急慢性炎症发展的同时，也促进了乳腺癌转移指标。然而，抗IL-6和抗IL-1β疗法在临床试验中对实体瘤并未产生显著效果。在此我们表明这三种细胞因子在表达上相互关联。利用柯蒂斯TCGA™数据集，我们确定OSM、IL-6和IL-1β的表达水平与乳腺癌患者生存率降低之间存在相关性（=0.6，=2.2×10）。重要的是，我们证实OSM以依赖STAT3信号传导的方式诱导雌激素受体阴性（ER-）乳腺癌细胞产生的IL-6至少增加4倍。此外，OSM诱导STAT3磷酸化，IL-1β促进p65磷酸化，以协同诱导ER-MDA-MB-231细胞中IL-6的分泌，在ER+MCF7人乳腺癌细胞中诱导程度较小。由于ER和STAT3之间先前已知的抑制性相互作用，ER+MCF7细胞中的诱导作用可能会降低。有趣的是，我们在MCF7细胞中发现，通过OSM和IL-1β处理，ER与STAT3的相互作用降低了50%，这表明ER在减轻STAT3介导的炎症级联反应中发挥作用。在此，我们为一种同时抑制多个靶点的乳腺癌治疗方案提供了理论依据，因为这些细胞因子具有许多重叠功能，会增加转移并恶化患者生存率。
