LncRNA H19/miR‐194/PFTK1 axis modulates the cell proliferation and migration of pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge due to its high mortality and morbidity; gene therapy might be a promising treatment for PDAC. The critical role of Wnt-signaling pathway in cancer pathogenesis has been widely recognized; cyclin-dependent kinase 14 (CDK14, PFTK1)-induced lowdensity lipoprotein receptor-related proteins 5/6 (LRP5/6) phosphorylation is an important issue in Wnt-signaling activation. Long noncoding RNA (LncRNA)-microRNA (miRNA)-messenger RNA (mRNA) modulating the pathogenesis of cancers has been regarded as a major mechanism. In the current study, upregulated lncRNAs positively correlated with PFTK1 were analyzed and selected using The Cancer Genome Atlas (TCGA) database. Of them, lncRNA H19 can activate Wnt signaling in cancers. In PDAC tissues, the expression of H19 and PFTK1 were upregulated; H19 knockdown suppressed the cell proliferation and migration of PDAC, while PFTK1 overexpression partially attenuated the suppressive effect of H19 knockdown. As analyzed by TCGA and predicted by online tools, miR-194 was negatively correlated with PFTK1 and might bind to both H19 and PFTK1, which was further confirmed by luciferase reporter and RNA immunoprecipitation assays. Moreover, the effect of H19 knockdown on PFTK1 protein and the cell proliferation and migration could be partially reversed by miR-194 inhibition; H19/miR-194 axis modulated PDAC cell proliferation and migration through PFTK1 downstream Wnt signaling. Results suggested that rescuing miR-194 expression in PDAC can inhibit lncRNA H19 and PFTK1 expression, subsequently suppressing PDAC cell proliferation and migration. Due to the complexity of the lncRNA-miRNA-mRNA network, further in vivo experiments examining potential side effects are needed in future study to explore the clinical application of these findings. K E Y W O R D S long noncoding RNA H19, miR-194, pancreatic ductal adenocarcinoma, Wnt signaling

Non-coding RNAs in Pancreatic Ductal Adenocarcinoma

“…MiR-675 reduces the activation of H19 by binding to the 3 ′ untranslated region (UTR) on E2F-1 mRNA and altering the expression of E2F-1 protein (50). In addition, the Wnt-signaling pathway is involved in regulating PDAC cell proliferation and migration via the H19/miR-194/PFFTK1 axis (51). H19 is also believed to play a role in cancer therapy and is the earliest lncRNA used in the treatment of PDAC.…”

Integrated analysis identifies a pathway-related competing endogenous RNA network in the progression of pancreatic cancer

“…Although a few studies have already assessed the role of ceRNA in the progression of PC [44,45], few studies focus on the pathway-related ceRNA axis using an Integrated analysis. Also, to our knowledge, it is the first study of PC that constructed a pathway-related ceRNA network in the progression of PC.…”

The multifaceted roles of long noncoding RNAs in pancreatic cancer: an update on what we know

“…In vitro experiments confirmed the predicted interaction between their nucleotide sequences. The observed inhibition of PDAC proliferation suggested that the H19/miR-194/PFTK1 axis in the WNT signaling pathway contributes to PC proliferation and migration [58]. In vivo experiments showed that the stable knockdown of H19 significantly suppressed the lung and liver metastatic potential of xenografts [8].…”