Abstract
ObjectivesIncreasing researches emphasize the importance of long non-coding RNAs (lncRNAs) in the development of endometrial cancer (EC). There is wide recognition that LINC00470 is a critical participant in the tumorigenesis of cancers such as gastric cancer and glioblastoma, but its possible effects on EC progression remain to be explored.MethodsWe collected EC tissues and cells, where the expression of LINC00470 was determined, and followed by the Kaplan-Meier analysis of EC patient survival. We next examined the effect of LINC00470 and phosphatase and tensin homolog (PTEN) on EC cell migration, invasion, tube formation in vitro, and angiogenesis in mice xenografted with tumor after gain- or loss-of-function treatments. RNA pull-down, Co-IP, and ChIP experiments were performed to analyze the targeting relationships among LINC00470, MYC and DNMT3a.ResultsLINC00470 was aberrantly upregulated in EC and its high expression correlated to prognosis of EC patients. LINC00470 promoted invasiveness, migration, and angiogenesis of EC cells, and facilitated tumorigenesis and metastasis in vivo, but those effects were reversed by up-regulating PTEN. Functionally, LINC00470 bound to MYC in EC and that LINC00470 stimulated the binding of MYC to DNMT3a, and thus recruited DNMT3a through MYC to promote PTEN methylation.ConclusionsOur findings revealed that LINC00470 stimulated PTEN methylation to inhibit its expression by MYC-induced recruitment of DNMT3a, thus aggravating EC.
Highlights
Endometrial cancer (EC) is the most frequently diagnosed gynecological cancer in developed nations [1]
We determined the LINC00470 expression in EC tissues and their matched adjacent normal tissues using Reverse Transcription-Quantitative Polymerase Chain Reaction (RT-qPCR), which showed that LINC00470 was highly expressed in the tissues of Grade 1, 2, and 3 EC compared with that in adjacent normal tissues, among
RT-qPCR results showed that treatment with sh-LINC00470-1 and sh-LINC00470-2 reduced the expression of LINC00470 in KLE cells, and treatment with oe-LINC00470 enhanced the expression of LINC00470 in HEC-1-B cells, which validated the successful infection of LINC00470 (Figure 2B)
Summary
Endometrial cancer (EC) is the most frequently diagnosed gynecological cancer in developed nations [1]. The annual incidence of this gynecological malignancy is increasing, claiming more and more lives [2]. Three quarters of patients with EC with early diagnosis have a five-year survival of about 75%, and mainly characterized by the aberrant uterine bleeding and vaginal secretions [3]. Elevated risk for EC is associated with age of 50 years, diabetes mellitus, or thyroid diseases, and principally due to excessive estrogen exposure [4]. Tumor angiogenesis supports the tumor progression due to its close association with tumor metastasis [5]. A comprehensive understanding of the pathophysiology of this malignancy is beneficial to facilitate early diagnosis and improve current treatment outcomes [6]. Identification of molecules involved in the pathophysiology such as tumor angiogenesis and metastasis is urgent
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