College of Pharmacy, Chosun University, Gwangju 61452, Korea.
Int J Mol Sci. 2021 Mar 8;22(5):2711. doi: 10.3390/ijms22052711.
IL-34 has been recently identified as a ligand for CSF1R that regulates various cellular processes including cell proliferation, survival, and differentiation. Although the binding of IL-34 to CSF1R modulates several cancer-driving signaling pathways, little is known about the role of IL-34/CSF1R signaling in breast cancer. Herein, we report that IL-34 induces epithelial cell transformation and breast tumorigenesis through activation of MEK/ERK and JNK/c-Jun pathways. IL-34 increased the phosphorylation of MEK1/2, ERK1/2, JNK1/2, and c-Jun through CSF1R in mouse skin epidermal JB6 C141 cells and human breast cancer MCF7 cells. IL-34 enhanced c-Fos and c-Jun promoter activity, resulting in increased AP-1 transactivation activity in JB6 Cl41 and MCF7 cells. Moreover, PIN1 enhanced IL-34-induced phosphorylation of MEK1/2, ERK1/2, JNK1/2, and c-Jun in JB6 Cl41 and MCF7 cells. Inhibition of PIN1 using juglone prevented the IL-34-induced transformation of JB6 C141 cells. Similarly, silencing of PIN1 reduced the IL-34-induced tumorigenicity of MCF7 cells. Consistent with these results, the synergistic model showed that treatment with juglone suppressed the IL-34-induced growth of tumors formed by 4T1 cells in BALB/c mice. Our study demonstrates the role of IL-34-induced MEK/ERK and JNK/c-Jun cascades in breast cancer and highlights the regulatory role of PIN1 in IL-34-induced breast tumorigenesis.
白细胞介素 34（IL-34）最近被鉴定为 CSF1R 的配体，调节包括细胞增殖、存活和分化在内的各种细胞过程。虽然 IL-34 与 CSF1R 的结合调节了几个促进癌症的信号通路，但对于 IL-34/CSF1R 信号在乳腺癌中的作用知之甚少。在此，我们报告 IL-34 通过激活 MEK/ERK 和 JNK/c-Jun 途径诱导上皮细胞转化和乳腺癌发生。IL-34 通过 CSF1R 在小鼠皮肤表皮 JB6 C141 细胞和人乳腺癌 MCF7 细胞中增加 MEK1/2、ERK1/2、JNK1/2 和 c-Jun 的磷酸化。IL-34 增强了 c-Fos 和 c-Jun 启动子活性，导致 JB6 Cl41 和 MCF7 细胞中 AP-1 转录激活活性增加。此外，PIN1 增强了 JB6 Cl41 和 MCF7 细胞中 IL-34 诱导的 MEK1/2、ERK1/2、JNK1/2 和 c-Jun 的磷酸化。使用胡桃醌抑制 PIN1 可防止 IL-34 诱导的 JB6 C141 细胞转化。同样，沉默 PIN1 降低了 IL-34 诱导的 MCF7 细胞的致瘤性。与这些结果一致，协同模型表明，用胡桃醌处理可抑制 IL-34 诱导的 BALB/c 小鼠 4T1 细胞形成的肿瘤的生长。我们的研究表明 IL-34 诱导的 MEK/ERK 和 JNK/c-Jun 级联在乳腺癌中的作用，并强调了 PIN1 在 IL-34 诱导的乳腺癌发生中的调节作用。
