2. Academic Validation
  3. GC-MSCs transcriptionally upregulate SALL4 in gastric cancer through miR-4669/TIMP3/β-catenin signaling

GC-MSCs transcriptionally upregulate SALL4 in gastric cancer through miR-4669/TIMP3/β-catenin signaling

  • Cell Signal. 2025 Jun:130:111668. doi: 10.1016/j.cellsig.2025.111668.
Jing Wen 1,  Xiaoli Cao 2,  Baocheng Zhou 3,  Fang Yang 1,  Xiang Wang 1,  Yuanyuan Li 1,  Xinlan Zhao 1,  Jingyu Mei 1,  Wei Zhu 1,  Li Sun 4,  Feng Huang 5,  Mei Wang 6
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province 212013, China.
  • 2 Department of Laboratory Medicine, Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu Province 226321, China.
  • 3 Department of Medical Laboratory, Lianyungang Maternal and Child Health Hospital, Lianyungang, Jiangsu Province 222000, China.
  • 4 Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan 215300, China.
  • 5 Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan 215300, China; Department of Clinical Laboratory, Maternal and Child Health Care Hospital of Kunshan, Suzhou, Jiangsu Province, China.
  • 6 Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province 212013, China. Electronic address: wangmei8417@163.com.
PMID: 39965736 DOI: 10.1016/j.cellsig.2025.111668
Abstract

Backgrounds: Gastric cancer-associated mesenchymal stem cells (GC-MSCs) as integral components of the tumor microenvironment potentiate gastric Cancer growth and metastasis. SALL4 is aberrantly upregulated in gastric Cancer and pivotal for malignant progression. Whether GC-MSCs is responsible for SALL4 upregulation and the underlying mechanisms remains elusive.

Methods: Cancer growth and metastasis capacities were assessed by cell colony formation assay, transwell assay, and epithelial-mesenchymal transition protein detection in vitro as well as subcutaneous xenograft and peritoneal metastasis models in vivo. SALL4 was measured by qPCR, western blot and immunohistochemistry staining. Gain- and loss-functional analysis were performed for miRNA and target gene. β-catenin signaling was assessed by immunofluorescence staining and Top/FopFlash luciferase assay. Transcriptional regulation was conducted using chemicals, luciferase reporter and ChIP assay. Clinical tissues and TCGA-STAD database were included for expression profile, correlation and clinical relevance analysis.

Results: GC-MSCs promoted gastric Cancer growth and metastasis along with elevation of SALL4 and miR-4669 in Cancer cells and tissues. Overexpression of miR-4669 mimicked GC-MSC effects, while miR-4669 knockdown eliminated their oncogenic roles. TIMP3 was identified as a target of miR-4669 and mediated its functions. TIMP3 overexpression counteracted GC-MSC-induced Cancer progression and SALL4 expression. GC-MSCs activated SALL4 transcription through the miR-4669/TIMP3/β-catenin pathway. The regulatory axis was aberrantly expressed in gastric Cancer tissues, correlated with each Other in certain Cancer tissues and associated with lymph node metastasis.

Conclusions: GC-MSCs transcriptionally upregulate SALL4 to facilitate gastric Cancer cell growth and metastasis via miR-4669/TIMP3/β-catenin pathway, highlighting the crucial role of GC-MSCs in the aberrant upregulation of SALL4.

Keywords

Gastric cancer; Mesenchymal stem cells; SALL4; Tumor microenvironment; microRNA.

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