Knockdown of WISP1/DKK1 restrains phenotypic plasticity in esophageal squamous cell carcinoma by suppressing epithelial–mesenchymal transition and stemness

• Published in: Clinical & translational oncology Vol. 27; no. 2; pp. 580 - 592
• Main Authors: Fu, C., Lu, Z., Shi, J., Liu, F., Su, X.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2025
• Subjects: Animals; Apoptosis; CCN Intercellular Signaling Proteins - genetics; CCN Intercellular Signaling Proteins - metabolism; CCN Intercellular Signaling Proteins - physiology; Cell Line, Tumor; Cell Movement; Cell Plasticity - genetics; Cell Proliferation; Epithelial-Mesenchymal Transition - genetics; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma - genetics; Esophageal Squamous Cell Carcinoma - metabolism; Esophageal Squamous Cell Carcinoma - pathology; Gene Knockdown Techniques; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - physiology; Male; Medicine; Medicine & Public Health; Mice; Mice, Nude; Neoplastic Stem Cells - pathology; Oncology; Phenotype; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins - physiology; Research Article; Wnt1 inducible signaling pathway protein 1; Phenotypic plasticity; Esophageal squamous cell carcinoma; Dickkopf-1; Metastasis
• ISSN: 1699-3055; 1699-3055
• DOI: 10.1007/s12094-024-03639-6

Objective Wnt-induced signaling protein 1 (WISP1) and Dickkopf-1 (DKK1) are highly expressed in esophageal squamous cell carcinoma (ESCC), but no direct connection was identified between them. Phenotypic plasticity is a hallmark of ESCC. This research intended to identify the association between WISP1 and DKK1 and their roles in the phenotypic plasticity of ESCC. Methods Genes differentially expressed in esophageal carcinoma were analyzed in the GEO database, followed by analyses of GO and KEGG enrichment to screen the hub gene. WISP1 expression and DKK1 secretion was assessed in ESCC tissues and cells. The tumor xenograft and in vivo metastasis models were established by injecting ESCC cells into nude mice. Functional deficiency and rescue experiments were conducted, followed by assays for cell proliferation, migration/invasion, stemness, epithelial–mesenchymal transition (EMT), and apoptosis, as well as tumor volume, weight, proliferation, stemness, and lung metastasis. The binding relationship and co-expression of WISP1 and DKK1 were determined. Results WISP1 and DKK1 were upregulated in ESCC cells and tissues, and WISP1 was enriched in the cell stemness and Wnt pathways. WISP1 knockdown subdued proliferation, migration/invasion, EMT activity, and stemness but enhanced apoptosis in ESCC cells. WISP1 knockdown restrained ESCC growth, proliferation, stemness, and metastasis in vivo. WISP1 bound to DKK1 in ESCC. DKK1 overexpression abolished the repressive impacts of WISP1 knockdown on the malignant behaviors of ESCC cells in vitro and of ESCC tumor in vivo. Conclusion Knockdown of WISP1/DKK1 restrains the phenotypic plasticity in esophageal squamous cell carcinoma by suppressing epithelial–mesenchymal transition and stemness.