Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy worldwide. As metastasis and malignant progression are primarily responsible for the poor clinical outcomes of PDAC, identifying key genes involved in these processes and the underlying molecular mechanisms of PDAC is vital. In this study, by analyzing TCGA PDAC data and matched GTEx data, we found that MYEOV expression is associated with poor survival in PDAC patients and higher in carcinoma tissues than in healthy tissues. Elevated levels of MYEOV led to enhanced cell proliferation, invasion and migration in vitro and in vivo. Transcriptome analysis results revealed that MYEOV mediates global alterations in gene expression profiles in PDAC cells. MiRNA-seq analysis showed that MYEOV regulates the expression levels of miR-17-5p and miR-93-5p, and its depletion resulted in reduced cell proliferation, invasion and migration, as observed in MYEOV-knockdown PDAC cells. These effects are likely due to the ability of MYEOV to regulate enrichment of the transcription factor MYC at the gene promoter regions of the two miRNAs. Furthermore, we identified a complex containing MYEOV and MYC in the nucleus, providing additional evidence for the association of MYEOV with MYC. Taken together, our results suggest that MYEOV promotes oncogenic miR-17/93-5p expression by associating with MYC, contributing to PDAC progression.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy originating in the human pancreas, with fewer than 7% of patients surviving past 5 years [1]
Myeloma overexpressed gene (MYEOV) overexpression is associated with poor patient survival in PDAC To identify the genes associated with PDAC survival, we performed survival analysis based on TCGA [44] and GTEx [45, 46] data integrated in GEPIA (Table S2)
Based on the expression profiles of MYEOV in the PDAC and non-cancerous pancreatic (NCP) tissue samples, the area under the ROC curve (AUC) was determined as 0.878 (95% confidence interval (CI): 0.839-0.918; Fig. 1d), indicating that this aberrantly expressed gene may be of great diagnostic value to distinguish PDAC from NCP tissues
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy originating in the human pancreas, with fewer than 7% of patients surviving past 5 years [1]. PDAC is a major clinical problem because it has the worst prognosis among all cancers [2]. This poor prognosis is largely due to a delayed diagnosis owing to the lack of any symptoms in its early stages of development, with a PDAC diagnosis often considered to be a “death sentence” to patients [3, 4]. Despite substantial advancements in understanding the molecular progression of PDAC, the pathogenesis and mechanisms of PDAC remain unclear, highlighting the need to identify novel targets that may contribute to the highly malignant phenotype of this cancer. The dysregulated expression of MYEOV in cancer patients has been associated with its tumorigenic properties, the molecular mechanisms underlying MYEOVmediated tumorigenesis, in PDAC, remain largely unknown
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