Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the leading causes of cancer mortality, and new therapeutic options are urgently needed. Long noncoding RNA H19 (H19) is known to promote PDAC progression, but the downstream genes of H19 are largely unknown. Five PDAC cell lines, nonmalignant pancreatic cells, TCGA, GEO-derived pancreatic tissues (malignant, n=413; nonmalignant, n=234), a pancreatic tissue array (n=96), and pancreatic tissues from our clinic (malignant, n=20; nonmalignant, n=20) were examined by a gene array, RT-qPCR, Western blotting, MTT, colony formation, wound-healing, siRNA-mediated gene silencing, bioinformatics, xenotransplantation, and immunohistochemistry assays. The cell cycle inhibitor, UHMK1, was identified to have the strongest correlation with H19. UHMK1 expression was enhanced in PDAC, and high UHMK1 expression correlated with tumor stage, and lower overall survival. siRNA-mediated UHMK1 downregulation inhibited progression signaling. siRNA-mediated downregulation of H19 or UHMK1 inhibited tumor proliferation and xenograft growth. Based on the correlation between UHMK1 expression and clinical parameters, we developed a nomogram that reliably predicts patient prognosis and overall survival. Together, we characterized UHMK1 as an H19-induced oncogene and verified it as a novel PDAC prognostic marker for overall survival.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer mortality worldwide and is characterized by late diagnosis, early metastasis, and high therapy resistance [1]
These results suggested that H19 drives the progression of PDAC through U2AF homology motif kinase 1 (UHMK1) and through several downstream genes simultaneously
We established a nomogram with the risk factor of UHMK1 expression and showed that UHMK1 is a reliable parameter and independent predictor of the overall survival of PDAC patients
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer mortality worldwide and is characterized by late diagnosis, early metastasis, and high therapy resistance [1]. Therapeutic options for PDAC are limited [2, 3], and improvement is urgently needed. LncRNAs epigenetically regulate gene expression by modulating transcriptional activities, posttranscriptional activities, genomic imprinting, and other biological processes [5]. The lncRNA H19 (H19) has been identified as a cancer promotor in different cancer types [6– 9]. H19 is highly expressed in PDAC, and it promotes proliferation, migration, and metastasis [6, 10–12]. We identified the innate anti-viral immunity gene APOBEC3G as a major H19 downstream gene [12, 13] and demonstrated that the downregulation of H19 or APOBEC3G by siRNA or the bioactive agent sulforaphane prevented H19-mediated PDAC progression features as demonstrated by assays for colony formation, migration, invasion, Smad phosphorylation and tumor xenograft growth [12]. The function of additional, yet unknown, H19 target genes needs to be clarified
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