Abstract
ObjectiveThe recurrence and metastasis of nasopharyngeal cancer (NPC) may be mainly attributed to the persistence of cancer stem cells (CSCs); however, the linkage mechanism has yet to be fully elucidated.MethodsThe levels of miR-4721, FOXA1, and Nanog expression in NPC were detected by in situ hybridization and immunohistochemistry. In vivo and in vitro metastasis assays confirmed miR-4721 promotes cell migration and invasion. Tumor spheroid formation assay, side population (SP) assay, and ALDEFLUOR assay verified miR-4721 regulates cancer stem cell-like properties. Luciferase reporter assay showed that miR-4721 directly regulates FOXA1 and FOXA1 effects the promoter activity of miR-4721 and Nanog. Chromatin immunoprecipitation (ChIP) analysis and electrophoresis mobility shift assay (EMSA) revealed that FOXA1 combined the promoter region of human miR-4721 and Nanog and the possible mechanism was also analyzed.ResultsIn this study, a new mechanism of NPC tumorigenesis related to miR-4721 was verified. We found that miR-4721, FOXA1 and Nanog control their expressions through a negative feedback loop and then activate the downstream regulator of stem cell signaling to promote the enrichment and metastasis of NPC stem cells.ConclusionThese findings elucidate that the feedback loop of miR-4721/FOXA1/Nanog can regulate stemness and metastasis in NPC and may provide an experimental theoretical basis for metastasis and treatment resistance in NPC.
Highlights
Cancer stem cells (CSCs) comprise a small part of tumor tissues capable of self-renewal, immortal proliferation, and differentiation
The relationship between miR-4721, FOXA1 and Nanog in Nasopharyngeal carcinoma (NPC) was confirmed, and we found that miR-4721, FOXA1, and Nanog regulated their expressions through a negative feedback loop and activate the downstream regulator of stem cell signaling to promote the stemness and metastasis of NPC cells
We found that aldehyde dehydrogenase 1 (ALDH1) + labeled cells were significantly increased among overexpressing miR-4721 HONE1 and SUNE1 cells compared with those control cells, and these results could be reversed when adding inhibitors to NPC cells overexpressing miR-4721(Fig. 1B)
Summary
Cancer stem cells (CSCs) comprise a small part of tumor tissues capable of self-renewal, immortal proliferation, and differentiation. They are the root cause of tumor recurrence, metastasis, and treatment tolerance [1, 2]. Cancer stem cells seem to be involved in all stages of Nasopharyngeal carcinoma (NPC) is a malignant tumor that originates from epithelial cells located in the nasopharynx [5]. The incidence of nasopharyngeal cancer has obvious regional and ethnic differences. Yellow people are most susceptible, and Caucasians are very rare. The incidence of nasopharyngeal cancer is the highest in East Asia and Africa, but rare in other regions.
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