In this study, we present novel molecular mechanisms by which FOXO1 functions as a tumor suppressor to prevent the pathogenesis of nasopharyngeal carcinoma (NPC). First, we observed that FOXO1 not only controlled tumor stemness and metastasis, but also sensitized NPC cells to cisplatin (DDP) in vitro and in vivo. Mechanistic studies demonstrated that FOXO1-induced miR-200b expression through the GSK3β/β-catenin/TCF4 network-mediated stimulation of ZEB1, which reduced tumor stemness and the epithelial–mesenchymal transition (EMT) signal. Furthermore, we observed FOXO1 interaction with MYH9 and suppression of MYH9 expression by modulating the PI3K/AKT/c-Myc/P53/miR-133a-3p pathway. Decreased MYH9 expression not only reduced its interactions with GSK3β, but also attenuated TRAF6 expression, which then decreased the ubiquitin-mediated degradation of GSK3β protein. Increased GSK3β expression stimulated the β-catenin/TCF4/ZEB1/miR-200b network, which increased the downstream tumor stemness and EMT signals. Subsequently, we observed that chemically synthesized cinobufotalin (CB) strongly increased FOXO1-induced DDP chemosensitivity by reducing MYH9 expression, and the reduction in MYH9 modulated GSK3β/β-catenin and its downstream tumor stemness and EMT signal in NPC. In clinical samples, the combination of low FOXO1 expression and high MYH9 expression indicated the worst overall survival rates. Our studies demonstrated that CB potently induced FOXO1-mediated DDP sensitivity by antagonizing its binding partner MYH9 to modulate tumor stemness in NPC.
Nasopharyngeal carcinoma (NPC) is prevalent in East and Southeast Asia. In a previous study, Epstein-Barr virus (EBV)-miR-BART22 induces tumor metastasis and stemness and is significantly involved in NPC progression. In the present study, we observed that miR-4721 is induced by EBV-miR-BART22 through phosphatidylinositol 3-kinase (PI3K)/AKT/c-JUN/Sp1 signaling to promote its transcription. In a subsequent study, we observed that miR-4721 serves as a potential oncogenic factor promoting NPC cell cycle progression and cell proliferation
in vitro
and
in vivo
. Mechanism analysis indicated that miR-4721 directly targetes GSK3β and reduces its expression, which therefore elevates β-catenin intra-nuclear aggregation and activates its downstream cell cycle factors, including CCND1 and c-MYC. In clinical samples, miR-4721 and GSK3β are respectively observed to be upregulated and downregulated in NPC progression. Elevated expression of miR-4721 is positively associated with clinical progression and poor prognosis. Our study first demonstrated that miR-4721 as an oncogene is induced by EBV-miR-BART22 via modulating PI3K/AKT/c-JUN/Sp1 signaling to target GSK3β, which thus activates the WNT/β-catenin-stimulated cell cycle signal and enhances the tumorigenic capacity in NPC. miR-4721 may be a potential biomarker or therapeutic target in NPC treatment in the future.
The changes in retinal thickness and visual function in type 2 diabetic patients without clinical evidence of diabetic retinopathy were evaluated. A total of 141 diabetic subjects without retinopathy and 158 healthy subjects were enrolled in this study. Superior macular ganglion cell complex thicknesses were significantly decreased in diabetic cases, and no significant peripapillary retinal nerve fiber layer thickness changes were observed. The contrast sensitivities at all space frequencies were significantly different between diabetic patients and controls. The mean P50 amplitude from pattern electroretinogram results was reduced significantly in the diabetic group. In the diabetic group, average superior ganglion cell complex thicknesses positively correlated with both contrast sensitivities at high spatial frequencies and P50 amplitudes. The results indicated that ganglion cell complex thickness and visual function changes could be observed in diabetic subjects before the onset of any significant diabetic retinopathy. Macular ganglion cell complex reduction occurred much earlier than peripapillary retinal nerve fiber layer thinning in diabetic patients without retinopathy. diabetes mellitus, diabetic retinopathy, retinal nerve fiber layer, retinal ganglion cell, contrast sensitivity, electroretinogram
Citation:Zhu TP, Ma J, Li YH, Zhang Z. Association between retinal neuronal degeneration and visual function impairment in type 2 diabetic patients without diabetic retinopathy. Sci China Life Sci, 2015, 58: 550 -555,
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.