Indiana University School of Medicine-Northwest, Gary, IN, 46408, USA.
The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Mol Biol Rep. 2024 Sep 17;51(1):988. doi: 10.1007/s11033-024-09927-2.
Nod2 is involved in innate immune responses to bacteria, regulation of metabolism, and sensitivity to cancer. A Nod2 polymorphism is associated with breast cancer, but the role of Nod2 in the development and progression of breast cancer is unknown.
Here, we tested the hypothesis that Nod2 protects mice from breast cancer using the 4T1 orthotopic model of mammary tumorigenesis. WT and Nod2 mice were injected with 4T1 mammary carcinoma cells and the development of tumors was monitored. A detailed analysis of the tumor transcriptome was performed and genes that were differentially expressed and pathways that were predicted to be altered between WT and Nod2 mice were identified. The activation of key signaling molecules involved in metabolism and development of cancer was studied.
Our data demonstrate that Nod2 mice had a higher incidence and larger tumors than WT mice. Nod2 mice had increased expression of genes that promote DNA replication and cell division, and decreased expression of genes required for lipolysis, lipogenesis, and steroid biosynthesis compared with WT mice. Nod2 mice also had lower expression of genes required for adipogenesis and reduced levels of lipids compared with WT mice. The tumors in Nod2 mice had decreased expression of genes associated with PPARα/γ signaling, increased activation of STAT3, decreased activation of STAT5, and no change in the activation of ERK compared with WT mice.
We conclude that Nod2 protects mice from the 4T1 orthotopic breast tumor, and that tumors in Nod2 mice are predicted to have increased DNA replication and cell proliferation and decreased lipid metabolism compared with WT mice.
Nod2 参与细菌的先天免疫反应、代谢调节以及对癌症的敏感性。Nod2 多态性与乳腺癌相关，但 Nod2 在乳腺癌的发生和发展中的作用尚不清楚。
在这里，我们使用 4T1 原位乳腺癌模型来检验 Nod2 保护小鼠免受乳腺癌的假说。将 WT 和 Nod2 小鼠注射 4T1 乳腺癌细胞，并监测肿瘤的发展情况。对肿瘤转录组进行了详细分析，确定了 WT 和 Nod2 小鼠之间差异表达的基因和预测的改变途径。研究了涉及代谢和癌症发展的关键信号分子的激活情况。
我们的数据表明，Nod2 小鼠的肿瘤发生率和肿瘤体积均高于 WT 小鼠。与 WT 小鼠相比，Nod2 小鼠中促进 DNA 复制和细胞分裂的基因表达增加，而脂肪分解、脂肪生成和类固醇生物合成所需的基因表达减少。与 WT 小鼠相比，Nod2 小鼠中脂肪生成所需的基因表达也减少，脂质水平降低。与 WT 小鼠相比，Nod2 小鼠的肿瘤中与 PPARα/γ 信号相关的基因表达降低，STAT3 的激活增加，STAT5 的激活减少，而 ERK 的激活没有变化。
我们得出结论，Nod2 保护小鼠免受 4T1 原位乳腺癌的侵袭，并且与 WT 小鼠相比，Nod2 小鼠的肿瘤预计具有更高的 DNA 复制和细胞增殖能力，以及更低的脂质代谢能力。
