IFNγ 通过诱导 JAK1/STAT1/p65 NFκB 依赖的白细胞介素-8 表达，导致卵巢癌细胞迁移增加。
IFNγ induces JAK1/STAT1/p65 NFκB-dependent interleukin-8 expression in ovarian cancer cells, resulting in their increased migration.
机构信息
Department of Biological Sciences, St. John's University, NY 11439, USA.
Department of Biological Sciences, St. John's University, NY 11439, USA.
出版信息
Int J Biochem Cell Biol. 2021 Dec;141:106093. doi: 10.1016/j.biocel.2021.106093. Epub 2021 Oct 6.
Abstract
Interferon-γ (IFNγ) is a pleiotropic cytokine that has a crucial role in immune response and tumor immunity. Because of its anti-tumor effects, IFNγ has been used in cancer treatment. However, IFNγ also has tumor-promoting functions that are less well understood. Here, we show that IFNγ induces expression of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8) in ovarian cancer (OC) cells. The IFNγ-induced IL-8 expression is dependent on JAK1, STAT1, and p65 NFκB, and is associated with an increased occupancy of K314/315 acetylated p65 NFκB and Ser-727 phosphorylated STAT1 at the IL-8 promoter. Neutralization of IL-8 using anti-IL-8 antibody reduces IFNγ-induced migration of OC cells, and their invasion ability in 3D spheroids. Together, these findings identify IL-8 as a novel target induced by IFNγ/JAK1/STAT1/p65 NFκB signaling, and indicate that the IFNγ-induced IL-8 contributes to IFNγ pro-tumorigenic effects in ovarian cancer cells.
摘要
干扰素-γ（IFNγ）是一种具有多种功能的细胞因子，在免疫反应和肿瘤免疫中起着至关重要的作用。由于其抗肿瘤作用，IFNγ已被用于癌症治疗。然而，IFNγ 也具有促进肿瘤生长的功能，但其机制尚不清楚。在这里，我们发现 IFNγ 可诱导卵巢癌细胞中促炎和促血管生成趋化因子白细胞介素-8（IL-8，CXCL8）的表达。IFNγ 诱导的 IL-8 表达依赖于 JAK1、STAT1 和 p65 NFκB，并且与 IL-8 启动子上 K314/315 乙酰化 p65 NFκB 和 Ser-727 磷酸化 STAT1 的占有率增加有关。使用抗 IL-8 抗体中和 IL-8 可减少 IFNγ 诱导的 OC 细胞迁移和它们在 3D 球体中的侵袭能力。总之，这些发现确定了 IL-8 是 IFNγ/JAK1/STAT1/p65 NFκB 信号诱导的新靶点，并表明 IFNγ 诱导的 IL-8 有助于 IFNγ 在卵巢癌细胞中的促肿瘤发生作用。
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