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.
Highlights
Cancer of the head and neck (HNC) is the sixth most common cancer worldwide, with over 500,000 new casesCancer stem-like cells (CSCs), called tumorinitiating cells, are a small population of tumor cells that have the capacity to self-renew like normal stem cells, initiate tumor and drive tumor growth, invasion and metastasis[4]
We hypothesized that Nanog has a major role in CD44(+)-head and neck squamous cell carcinomas (HNSCCs) cells as a self-renewal protein and a new “master gene” of tumorigenesis in HNSCC
We first confirmed that all HNSCC cell lines (SCC-15, squamous cell carcinomas (SCC)-25, and QLL-1) when grown as spheroids showed increased expression of CD44, whereas the levels of other putative casesCancer stem-like cells (CSCs) markers such as CD24 and CD133 were not reliably increased
Summary
Cancer of the head and neck (HNC) is the sixth most common cancer worldwide, with over 500,000 new casesCancer stem-like cells (CSCs), called tumorinitiating cells, are a small population of tumor cells that have the capacity to self-renew like normal stem cells, initiate tumor and drive tumor growth, invasion and metastasis[4]. Huang et al Cell Death and Disease (2020)11:266 tumors in non-obese diabetic/severe combined immunodeficient mice in vivo[5]. In 2007, Prince et al.[16] first identified a cellular subpopulation in head and neck tumors expressing the surface marker CD44 with stem-like characteristics; these cells were capable of reproducing when implanted into immunosuppressed mice. CD44 has a critical role in cell metastasis and malignancy, and is involved in multiple steps[17,18]. In head and neck squamous cell carcinomas (HNSCCs), CD44 has been reported to be involved in metastasis and has been identified as a CSC marker. Critical molecular mechanisms and roles that maintain the ‘stemness’ of CSCs in the subset of patients with advanced HNSCC with high CD44 expression are largely unknown
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