Abstract：
Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) has been identified as a crucial immune suppressor in human cancers, comparable to programmed cell death 1 ligand (PD-L1). However, the regulatory mechanisms underlying its transcriptional upregulation in human cancers remain largely unknown. Here, we show that the transcription factors ETS-1 and ETS-2 bound to the Siglec-15 promoter to enhance transcription and expression of Siglec-15 in hepatocellular carcinoma (HCC) cells and that transforming growth factor β-1 (TGF-β1) upregulated the expression of ETS-1 and ETS-2 and facilitated the binding of ETS-1 and ETS-2 to the Siglec-15 promoter. We further demonstrate that TGF-β1 activated the Ras/C-Raf/MEK/ERK1/2 signaling pathway, leading to phosphorylation of ETS-1 and ETS-2, which consequently upregulates the transcription and expression of Siglec-15. Our study defines a detailed molecular profile of how Siglec-15 is transcriptionally regulated which may offer significant opportunity for therapeutic intervention on HCC immunotherapy.
摘要：
唾液酸结合免疫球蛋白样凝集素15（Siglec-15）已被确定为人类癌症的关键免疫抑制剂，与程序性细胞死亡1配体（PD-L1）相当。然而,其在人类癌症中转录上调的潜在调控机制仍然未知.这里,我们显示转录因子ETS-1和ETS-2与Siglec-15启动子结合以增强Siglec-15在肝细胞癌（HCC）细胞中的转录和表达，并且转化生长因子β-1（TGF-β1）上调ETS-1和ETS-2的表达，并促进ETS-1和ETS-2与Siglec-15启动子的结合。我们进一步证明TGF-β1激活了Ras/C-Raf/MEK/ERK1/2信号通路,导致ETS-1和ETS-2的磷酸化，从而上调Siglec-15的转录和表达。我们的研究定义了Siglec-15如何转录调控的详细分子谱，这可能为HCC免疫治疗的治疗干预提供重要机会。
