Transcriptional Regulation of Siglec-15 by ETS-1 and ETS-2 in Hepatocellular Carcinoma Cells

  • Int J Mol Sci. 2023 Jan 2;24(1):792. doi: 10.3390/ijms24010792.
Kaiqin Sheng  1 ,  Yuecheng Wu  1 ,  Hanbin Lin  1 ,  Menghan Fang  1 ,  Chaorong Xue  1 ,  Xu Lin  1  2 ,  Xinjian Lin  1
Affiliations
  • 1. Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou 350122, China.
  • 2. Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou 350122, China.
PMID: 36614238 DOI: 10.3390/ijms24010792
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.

Keywords
ETS-1; ETS-2; HCC; Siglec-15; TGF-β1; transcriptional regulation.
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