Abstract
Long noncoding RNAs (lncRNAs) have been reported to be involved in a variety of human diseases, including cancers. However, their mechanisms have not yet been fully elucidated. We investigated lncRNA changes that may be associated with pancreatic cancer (PC) by analyzing published microarray data, and identified AGAP2-AS1 as a relatively overexpressed lncRNA in PC tissues. qRT-PCR assays were performed to examine expression levels of AGAP2-AS1. MTT assays, colony formation assays, and EdU assays were used to determine the proliferative capacity of cells. Flow cytometry and TUNEL assays were used to study the regulation of AGAP2-AS1 in the cell cycle and apoptosis. Transwell experiments were used to study changes in cell invasion and metastasis, and a nude mouse model was established to assess the effects of AGAP2-AS1 on tumorigenesis in vivo. RNA sequencing was performed to probe AGAP2-AS1-related pathways. Subcellular fractionation and FISH assays were used to determine the distribution of AGAP2-AS1 in PC cells, and RIP and ChIP were used to determine the molecular mechanism of AGAP2-AS1-mediated regulation of potential target genes. Increased expression of AGAP2-AS1 was associated with tumor size and pathological stage progression in patients with PC. RREB1 was found to activate transcription of AGAP2-AS1 in PC cells. AGAP2-AS1 affected proliferation, apoptosis, cycle arrest, invasion, and metastasis of PC cells in vitro, and AGAP2-AS1 regulated PC proliferation in vivo. Furthermore, AGAP2-AS1 epigenetically inhibited the expression of ANKRD1 and ANGPTL4 by recruiting zeste homolog 2 (EZH2), thereby promoting PC proliferation and metastasis. In summary, our data show that RREB1-induced upregulation of AGAP2-AS1 regulates cell proliferation and migration in PC partly through suppressing ANKRD1 and ANGPTL4 by recruiting EZH2. AGAP2-AS1 represents a potential target for the diagnosis and treatment of PC in the future.
Highlights
Introduction As reported in CancerStatistics (2018), pancreatic cancer (PC) is the fourth most common cause of cancerrelated deaths in the USA and other Western countries, and is predicted to become the second leading cause in 10 years
AGAP2-AS1 expression is upregulated in PC and is associated with poor prognosis Based on bioinformatics analysis, we downloaded a microarray data set (GSE16515) containing 16 human PC tissues and 16 corresponding para-cancerous tissues from the Gene Expression Omnibus (GEO), and searched for Long noncoding RNAs (lncRNAs) that were significantly differentially expressed in PC we selected lncRNAs for which P < 0.05 and logFC > 0 for the difference between human PC tissues and corresponding para-cancerous tissues in original normalized signal data
We found that lncRNA AGAP2-AS1 (AGAP2 antisense RNA 1) was upregulated in the GSE16515 data set (Fig. 1b)
Summary
Statistics (2018), pancreatic cancer (PC) is the fourth most common cause of cancerrelated deaths in the USA and other Western countries, and is predicted to become the second leading cause in 10 years. Its average annual incidence rate in the United States is 12.5 per 100,000 (3% of all cancers), but the mortality rate is very high Hui et al Cell Death and Disease (2019)10:207. It is difficult to diagnose PC at an early stage. There are currently no conventional biomarkers that are suitable for use in the diagnosis of PC1. There is an urgent need to further study the mechanisms underlying PC occurrence and progression, to identify biomarkers with early diagnostic value and to find new and promising therapeutic targets
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