RETRACTED ARTICLE: ERK1/2-Nanog signaling pathway enhances CD44(+) cancer stem-like cell phenotypes and epithelial-to-mesenchymal transition in head and neck squamous cell carcinomas

Abstract

Head and neck squamous cell carcinomas (HNSCCs) harbor a subset of cells that are CD44(+) and present with malignancy and radiotherapy resistance. As a key regulator of self-renewal, Nanog expression not only determines cell fate in pluripotent cells but also mediates tumorigenesis in cancer cells; thus, we examined the role of Nanog in CD44 (+) HNSCC. Three HNSCC cell lines, tumor xenografts, and patient tumors were examined. Nanog levels were significantly higher in CD44(+) HNSCC spheroids than in CD44(−) spheroids, and further increased when grown as spheroids to enrich for CSCs. CD44(+) spheroids showed a 3.4-7.5-fold increase in migration and invasion compared with CD44(−) spheroids and were resistant to radiation therapy, which was reversed by inhibiting Nanog. Nanog knockdown also decreased spheroid formation by 66.5-68.8%. Moreover, a phosphokinase array identified upregulated ERK1/2 signaling in CD44(+) HNSCC cells compared with that in CD44(−) cells. ERK1/2 signaling was found to regulate Nanog expression, aiding tumor progression, metastasis, and radiotherapy resistance. In xenograft models, the combination of radiation and Nanog or ERK1/2 inhibition inhibited tumor growth by 75.6% and 79.1%, respectively. In lung metastasis models, CD44(+) cells injected into the tail vein of mice led to significantly more lung metastases and higher Nanog expression level compared with that by ERK1/2-knockdown CD44(+) cells. Finally, in tumor tissues, CD44 and Nanog expression levels were correlated with tumorigenesis in HNSCC patients. Thus, targeting Nanog and the ERK1/2 signaling pathway may prevent or reverse CSC phenotypes and epithelial-mesenchymal transition that drive tumor progression, metastasis, and radiotherapy resistance in HNSCC.

The first crested duck genome reveals clues to genetic compensation and crest cushion formation

“…Thus, the crested duck can form a protective tissue on fragile crested tissue. NANOG, which is involved in the development of neural crest stem cells, has been shown to play a role in the pathogenesis of many cancers by regulating cell proliferation, invasion, and metastasis [36,37]. Therefore, we suggest that NANOG could be a key gene in DNA damage repair and the GCR in CC ducks.…”

Ephrin A4-ephrin receptor A10 signaling promotes cell migration and spheroid formation by upregulating NANOG expression in oral squamous cell carcinoma cells

“…4 ). Similarly, Yin et al reported that co-expression of OCT4 and NANOG induced development of CSC characteristics and enhanced EMT in hepatocellular carcinoma, and Huang et al showed that ERK-NANOG signaling promoted CSC phenotypes and EMT in HNSCC 36 , 37 .…”

Nanog is a promising chemoresistant stemness marker and therapeutic target by iron chelators for esophageal cancer

“…29,37,38 CD44 has been reported to interact with Nanog through ERK1/2 and β-catenin pathways. 39,40 These candidate drugs for CSCs could not suppress stemness potential, at least in esophageal cancer. Here, it is appropriate to discuss stemness suppression by iron chelators.…”