Abstract
Pseudogenes have been reported to play oncogenic or tumor-suppressive roles in cancer progression. However, the molecular mechanism of most pseudogenes in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Herein, we characterized a novel pseudogene-miRNA-mRNA network associated with PDAC progression using bioinformatics analysis. After screening by dreamBase and GEPIA, 12 up-regulated and 7 down-regulated differentially expressed pseudogenes (DEPs) were identified. According to survival analysis, only elevated AK4P1 indicated a poor prognosis for PDAC patients. Moreover, we found that AK4 acts as a cognate gene of AK4P1 and also predicts worse survival for PDAC patients. Furthermore, 32 miRNAs were predicted to bind to AK4P1 by starBase, among which miR-375 was identified as the most potential binding miRNA of AK4P1. A total of 477 potential target genes of miR-375 were obtained by miRNet, in which 49 hub genes with node degree ≥ 20 were identified by STRING. Subsequent analysis for hub genes demonstrated that YAP1 may be a functional downstream target of AK4P1. To confirmed the above findings, microarray, and qRT-PCR assay revealed that YAP1 was dramatically upregulated in both PDAC cells and tissues. Functional experiments showed that knockdown of YAP1 significantly suppressed PDAC cells growth, increased apoptosis, and decreased the ability of invasion. In conclusion, amplification of AK4P1 may fuel the onset and development of PDAC by targeting YAP1 through competitively binding to miR-375, and serve as a promising biomarker and therapeutic target for PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) has been the seventh major cause of cancer-related deaths worldwide with an estimated 466 003 deaths occurring in 2020 [1].Despite the development of novel screening and therapeutic strategies in recent decades, the prognosis of pancreatic ductal adenocarcinoma (PDAC) patients is not optimistic, and the 5-year survival rate remains less than 9% [2–4]
We found that 12 upregulated and 7 downregulated differentially expressed pseudogenes (DEPs) were consistent with the above data from dreamBase (Figure 1B and Supplementary Figure 1)
The prognostic roles of the above 19 DEPs in PDAC were studied by gene expression profiling interactive analysis (GEPIA) (Table 1)
Summary
Pancreatic ductal adenocarcinoma (PDAC) has been the seventh major cause of cancer-related deaths worldwide with an estimated 466 003 deaths occurring in 2020 [1].Despite the development of novel screening and therapeutic strategies in recent decades, the prognosis of PDAC patients is not optimistic, and the 5-year survival rate remains less than 9% [2–4]. Increasing evidence have reported that the majority of pseudogenes play oncogenic or tumor-suppressive roles in various cancers, and maybe act as promising diagnostic biomarkers and effective therapeutic targets [15, 16]. Recent studies have highlighted the importance of pseudogenes in gene regulation, which may affect many aspects of tumorigenesis and the development of cancers, including PDAC [17–20]. Pseudogene DUXAP8 promotes PDAC cells growth by epigenetically silencing CDKN1A and KLF2 [21]. Depletion of pseudogene ZFP91P significantly decreased PDAC cells proliferation and migration capacities by altering beta-catenin and vimentin expression [23]. SUMO1P3 could promote PDAC cells proliferation, migration, and invasion via the EMT signaling pathway [24]. Recent studies identified that pseudogenes AC093616.1, AC009951.1, TMEM183B and PABPC1P4 played critical roles in PDAC metastasis through regulating miR-30d-5p/GJA1 axis [26]. The pseudogene-miRNA-mRNA networks in PDAC have not yet been fully elucidated
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