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. 2025 Feb;27(2):580-592.
doi: 10.1007/s12094-024-03639-6. Epub 2024 Aug 2.

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

C Fu  1 , Z Lu  1 , J Shi  2 , F Liu  3 , X Su  4
Affiliations

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

C Fu et al. Clin Transl Oncol. 2025 Feb.

Abstract

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.

Keywords: Dickkopf-1; Esophageal squamous cell carcinoma; Metastasis; Phenotypic plasticity; Wnt1 inducible signaling pathway protein 1.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Research involving human participants and/or animals: All experimental designs and protocols involving animals were approved by the Animal Ethics Committee of Southeast University (approval 20210301085) and complied with the recommendations of the academy’s animal research guidelines. Informed consent: This study design was reviewed and approved by the Medical Ethics Committee of the Zhongda Hospital, Southeast University (No. 2021ZDKYSB121). In accordance with the principles of the Declaration of Helsinki. Participants, either as individuals or as uardians, gave written informed consent.

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