Diabetes mellitus (DM) has shown a trend of reaching pandemic levels in the world. [1][2][3] It has rapidly become a global health problem.Diabetic retinopathy (DR) is the most common microvascular complication of type 2 diabetes mellitus (T2D) and the most frequent. 4 DR is one of the major eye diseases causing blindness in people aged 50 years and above. 5 Its basic pathological changes are destruction of blood retinal barrier (BRB) and the formation of retinal neovascularization. 6 Studies 7 on the prevalence of DR in China show that between 9.4% and 43.1% of patients with diabetes are diagnosed with DR. In addition, DR is always asymptomatic before entering the later stage because DR seriously harms human health and the economic sustainability of the national health system, both for individual vision
Background: Cancer stem cells are responsible for tumor initiation and progression in various types of cancer, while, although the existence of retinoblastoma stem cells had been reported, the mechanisms supporting retinoblastoma stemness are poorly understood. In this study, a modi ed method for isolating retinoblastoma stem-like cells for mechanistic study was rst established and an important mechanism underlying SOX2-drived retinoblastoma stemness was subsequently revealed.Methods: The retinoblastoma stem-like cells were isolated by single cell cloning in combination of examination of sphere-forming capacities. The stemness of isolated retinoblastoma stem-like cells were characterized by sphere-forming capacities and the expression of cancer stem cell markers. The SOX2 gene was overexpressed or knocked down by lentivirus system. The transcriptional regulation was identi ed by qRT-PCR, luciferase reporter, nuclear run-on and DNA pull down assay. Spearman analysis was employed for correlation analysis of genes in tumor tissues of retinoblastoma patients.Results: The isolated retinoblastoma stem-like cells exhibited signi cantly enhanced sphere-forming capacity and constantly higher levels of CD44, ABCG2, SOX2 and PAX6, but not CD133. SOX2 positively regulated the stemness of retinoblastoma stem-like cells as identi ed by gene manipulation technology. SOX2 directly binds to the promoters of WWTR1 and YAP1, transcriptionally activates WWTR1 and YAP1, and thereby activating Hippo/YAP signaling. Knockdown of WWTR1 or YAP1 partially abolished the effect of SOX2 on the stemness of retinoblastoma stem-like cells.Conclusion: An effective method for isolation of retinoblastoma stem-like cells was established. The mechanistic study demonstrated that SOX2, as a key deriver, maintains retinoblastoma stemness by activating Hippo/YAP signaling. Inhibition of Hippo/YAP signaling would be an effective strategy for human retinoblastoma caused by aberrant upregulation of SOX2.
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