Department of Physiology, University of Siena, Via Aldo Moro, 53100 Siena, Italy.
Eur J Cancer. 2010 Dec;46(18):3400-8. doi: 10.1016/j.ejca.2010.07.044. Epub 2010 Aug 26.
The casual relationship between inflammation and tumour progression has been widely accepted and the etiology of breast cancer has been associated with inflammatory processes. Interleukin (IL)-1β, besides its central role in inflammation, has also been recognised as a powerful player in tumour progression, angiogenesis and invasiveness. Recently, there has been considerable interest in understanding the non-hypoxic upregulation of the hypoxia-inducible factor (HIF)-1α by IL-1 in neoplastic cells since aberrant expression of HIF-1α correlates with tumour progression. Here, using the highly invasive human breast cancer cell line MDAMB231, we studied the effect of IL-1β on tumour cell migration along with HIF-1α accumulation. We observed that non-hypoxic induction of HIF-1α by IL-1β in MDAMB231 was associated with increased cell migration, paralleled by upregulation of p38 MAPK phosphorylation and CXCL8/CXCR1 expression. Inhibition of HIF-1α by siRNA resulted in a significant reduction of CXCR1 expression and IL-1β-induced cell migration in MDAMB231 cells, thus confirming a role of HIF-1α in the non-hypoxic-IL-1β-dependent induction of migratory potentials. Our observation that IL-1 induces HIF-1α accumulation in MDAMB231 cells was confirmed in tumour cells growing in vivo using an experimental approach, mimicking the endogenous release of IL-1 in mice bearing MDAMB231 xenografts. Our in vivo data, along with the fact that inhibition of HIF-1α resulted in the decrease of IL-1β-promoted cell migration, further support the link between inflammation and cancer. The overall results may have important implications in those therapeutic approaches aimed to inhibit IL-1-mediated activities in tumour cells, specifically in breast cancer.
炎症与肿瘤进展之间的偶然关系已被广泛接受，乳腺癌的病因与炎症过程有关。白细胞介素（IL）-1β 除了在炎症中起核心作用外，还被认为是肿瘤进展、血管生成和侵袭性的强大参与者。最近，人们对理解 IL-1 在肿瘤细胞中非缺氧诱导缺氧诱导因子（HIF）-1α 的上调产生了浓厚的兴趣，因为 HIF-1α 的异常表达与肿瘤进展相关。在这里，我们使用高度侵袭性的人乳腺癌细胞系 MDAMB231，研究了 IL-1β 对肿瘤细胞迁移和 HIF-1α 积累的影响。我们观察到，IL-1β 在 MDAMB231 中非缺氧诱导的 HIF-1α 与细胞迁移增加有关，同时 p38 MAPK 磷酸化和 CXCL8/CXCR1 表达上调。siRNA 抑制 HIF-1α 导致 CXCR1 表达和 IL-1β 诱导的 MDAMB231 细胞迁移显著减少，从而证实 HIF-1α 在非缺氧-IL-1β 依赖性诱导迁移潜能中的作用。我们观察到，IL-1 在 MDAMB231 细胞中诱导 HIF-1α 积累，这在使用实验方法在体内生长的肿瘤细胞中得到了证实，该方法模拟了在携带 MDAMB231 异种移植物的小鼠中内源性释放 IL-1。我们的体内数据，以及 HIF-1α 抑制导致 IL-1β 促进细胞迁移减少的事实，进一步支持了炎症与癌症之间的联系。这些结果可能对旨在抑制肿瘤细胞中 IL-1 介导的活性的治疗方法具有重要意义，特别是在乳腺癌中。
