Abstract
BackgroundRecurrence and distant metastasis are still the main factors leading to treatment failure for malignant tumors including nasopharyngeal carcinoma (NPC). Therefore, elucidating the molecular mechanisms underlying nasopharyngeal carcinoma metastasis is of great clinical significance for targeted gene therapy and prognostic evaluation. PinX1, a tumor suppressor gene, was previously demonstrated to be a powerful tool for targeting telomerase in order to resist malignant tumor proliferation and migration. The aim of this study was to explore the mechanism through which PinX1 regulates epithelial–mesenchymal transition (EMT) and tumor metastasis in NPC and investigate its clinical significance and biological role with respect to disease progression.MethodsCell Counting Kit-8 (CCK8), Transwell assays, Colony formation analysis and Xenograft tumorigenicity assay were used to measure the nasopharyngeal CD133+ cancer stem cell proliferation, migration, and invasion abilities. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot assays were conducted to investigate the underlying mechanism that PinX1 inhibits cell proliferation, migration, and invasion via regulating EMT in nasopharyngeal CD133+ CSCs.ResultsWe found that the overexpression of PinX1 and P53 inhibited cell proliferation, migration, and invasion, but that the inhibition of miR-200b blocked these effects, in nasopharyngeal CD133+ cancer stem cells (CSCs). Mechanistic investigations elucidated that PinX1 inhibits cell proliferation, migration, and invasion by regulating the P53/miR-200b-mediated transcriptional suppression of Snail1, Twist1, and Zeb1, consequently inhibiting EMT in nasopharyngeal CD133+ CSCs.ConclusionsOur findings indicate that PinX1 inhibits cell proliferation, migration, and invasion via P53/miR-200b-regulated EMT in the malignant progression of human NPC, which might suggest novel clinical implications for disease treatment.
Highlights
Recurrence and distant metastasis are still the main factors leading to treatment failure for malignant tumors including nasopharyngeal carcinoma (NPC)
Third passages of nasopharyngeal cancer stem cells (CSCs) at the logarithmic phase of growth were divided into the following groups: CD133− CSCs (CD133− CSCs without any transfection), blank (CD133+ CSCs without any transfection), negative control (NC, CD133+ CSCs transfected with empty vector), Pin2/telomeric repeat factor 1-interacting telomerase inhibitor 1 (PinX1) overexpression (CD133+ CSCs transfected with pcDNA3.0-PinX1), P53 overexpression CD133+ CSCs transfected with pcDNA3.0-P53), miR-200b inhibitor (CD133+ CSCs transfected with miR-200b inhibitor), PinX1 overexpression + P53 overexpression (CD133+ CSCs transfected with pcDNA3.0-PinX1 and pcDNA3.0P53) and PinX1 overexpression + miR-200b inhibitor (CD133+ CSCs transfected with pcDNA3.0-PinX1 and miR-200 inhibitor)
PinX1 is downregulated and epithelial–mesenchymal transition (EMT) is promoted in nasopharyngeal CD133+ CSCs The expression of PinX1, E-cadherin, Vimentin, Snail1, Twist1, and Zeb1 in nasopharyngeal CD133+ CSCs and CD133− cells was determined by qRT-PCR and western blot analysis
Summary
Recurrence and distant metastasis are still the main factors leading to treatment failure for malignant tumors including nasopharyngeal carcinoma (NPC). Zhang et al [11] demonstrated that leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a stem cell marker for colon cancer and gastric cancer, can promote EMT by activating the Wnt/beta-catenin pathway in glioma stem cells. These findings suggest a vital link between EMT and the stemness of tumor cells [11, 12]. It is imperative to investigate the molecular mechanisms that drive EMT and tumorinitiating capacity, which might have significant implications for the exploration of new therapeutic targets for the treatment of epithelial malignancies and metastasis
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