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.
CONCLUSIONS: Knockdown of WISP1/DKK1 restrains the phenotypic plasticity in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition and stemness.
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.
CONCLUSIONS: Knockdown of WISP1/DKK1 restrains the phenotypic plasticity in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition and stemness.
摘要：
目的：Wnt诱导信号蛋白1（WISP1）和Dickkopf-1（DKK1）在食管鳞状细胞癌（ESCC）中高表达，但他们之间没有直接联系.表型可塑性是ESCC的标志。本研究旨在确定WISP1和DKK1之间的关联及其在ESCC表型可塑性中的作用。
方法：在GEO数据库中分析了食管癌中差异表达的基因，随后分析GO和KEGG富集以筛选hub基因。在ESCC组织和细胞中评估WISP1表达和DKK1分泌。通过将ESCC细胞注射到裸鼠中，建立了肿瘤异种移植和体内转移模型。进行了功能缺陷和抢救实验，然后进行细胞增殖试验,迁移/入侵，stemness,上皮-间质转化（EMT），和细胞凋亡，以及肿瘤体积，体重,扩散,stemness,和肺转移。确定了WISP1和DKK1的结合关系和共表达。
结果：在ESCC细胞和组织中WISP1和DKK1上调，和WISP1富集在细胞干性和Wnt途径中。WISP1敲低抑制增殖，迁移/入侵，EMT活动,和干性，但增强了ESCC细胞的凋亡。WISP1敲除抑制了ESCC的生长，扩散,stemness,和体内转移。在ESCC中WISP1与DKK1结合。DKK1过表达消除了WISP1敲低对体外ESCC细胞和体内ESCC肿瘤恶性行为的抑制作用。
结论：敲除WISP1/DKK1通过抑制上皮-间质转化和干性来抑制食管鳞状细胞癌的表型可塑性。
方法：在GEO数据库中分析了食管癌中差异表达的基因，随后分析GO和KEGG富集以筛选hub基因。在ESCC组织和细胞中评估WISP1表达和DKK1分泌。通过将ESCC细胞注射到裸鼠中，建立了肿瘤异种移植和体内转移模型。进行了功能缺陷和抢救实验，然后进行细胞增殖试验,迁移/入侵，stemness,上皮-间质转化（EMT），和细胞凋亡，以及肿瘤体积，体重,扩散,stemness,和肺转移。确定了WISP1和DKK1的结合关系和共表达。
结果：在ESCC细胞和组织中WISP1和DKK1上调，和WISP1富集在细胞干性和Wnt途径中。WISP1敲低抑制增殖，迁移/入侵，EMT活动,和干性，但增强了ESCC细胞的凋亡。WISP1敲除抑制了ESCC的生长，扩散,stemness,和体内转移。在ESCC中WISP1与DKK1结合。DKK1过表达消除了WISP1敲低对体外ESCC细胞和体内ESCC肿瘤恶性行为的抑制作用。
结论：敲除WISP1/DKK1通过抑制上皮-间质转化和干性来抑制食管鳞状细胞癌的表型可塑性。
