Pseudogene AK4P1 promotes pancreatic ductal adenocarcinoma progression through relieving miR-375-mediated YAP1 degradation

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.

<i>MiR-375</i> Inhibitor Alleviates Inflammation and Oxidative Stress by Upregulating the <i>GPR39</i> Expression in Atherosclerosis

“…39) The amplification of AK4P1 may promote the development and progression of pancreatic ductal adenocarcinoma by binding miR-375 to target YAP1. 40) The activation of NF-κB1 signalling downregulates the expressions of miR-375 and miR-455, thereby upregulating the TRPV1 protein level leading to lumbar neuropathic pain. 41) Our study confirmed that the miR-375 inhibitor improved inflammation and oxidative stress in atherosclerosis by targeting GPR 39, but the factors regulating miR-375 were unknown, which is a limitation of this study and deserves further investigation.…”

Integration of RNA-Seq and Machine Learning Identifies Hub Genes for Empagliflozin Benefitable Heart Failure with Reduced Ejection Fraction

“…GTF2IP14 is classified as a pseudogene of GTF2I, which is a DNA sequence in the genome resembling a normal gene but not expressed. 23 Traditionally, pseudogenes were considered functionless. However, recent studies suggest that pseudogenes may play crucial roles in various diseases through true genes.…”

Functional and Potential Therapeutic Implication of MicroRNAs in Pancreatic Cancer

“…Numerous other tumor-suppressive miRNAs, including miR-383, miR-375, miR-216b, miR-455, miR-202, and miR-494, were shown to be downregulated in the pancreatic cancer landscape. The underexpression or loss of expression of these miRNAs plays a substantial role in the progression of the disease by impacting multiple signaling pathways, such as AK4P1/SP1, c-MYC/SIRT1, the Wnt/β-catenin pathway, and the DLEU2/SMAD2 pathway, that lead to cancer cell proliferation, invasion, metabolism, and immune responses [53][54][55][56][57]. In the complex landscape of pancreatic cancer, these miRNAs bear promise as prognostic markers and potential targets for therapeutic intervention.…”