Dataset Information

Long noncoding RNA NORAD regulates transforming growth factor-? signaling and epithelial-to-mesenchymal transition-like phenotype.

ABSTRACT: Long noncoding RNAs are involved in a variety of cellular functions. In particular, an increasing number of studies have revealed the functions of long noncoding RNA in various cancers; however, their precise roles and mechanisms of action remain to be elucidated. NORAD, a cytoplasmic long noncoding RNA, is upregulated by irradiation and functions as a potential oncogenic factor by binding and inhibiting Pumilio proteins (PUM1/PUM2). Here, we show that NORAD upregulates transforming growth factor-? (TGF-?) signaling and regulates TGF-?-induced epithelial-to-mesenchymal transition (EMT)-like phenotype, which is a critical step in the progression of lung adenocarcinoma, A549 cells. However, PUM1 does not appear to be involved in this process. We thus focused on importin ?1 as a binding partner of NORAD and found that knockdown of NORAD partially inhibits the physical interaction of importin ?1 with Smad3, inhibiting the nuclear accumulation of Smad complexes in response to TGF-?. Our findings may provide a new mechanism underlying the function of NORAD in cancer cells.

SUBMITTER: Kawasaki N

PROVIDER: S-EPMC6029837 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Long noncoding RNA NORAD regulates transforming growth factor-β signaling and epithelial-to-mesenchymal transition-like phenotype.

Kawasaki Natsumi N Miwa Toshiki T Hokari Satoshi S Sakurai Tsubasa T Ohmori Kazuho K Miyauchi Kensuke K Miyazono Kohei K Koinuma Daizo D

Cancer science 20180529 7

Long noncoding RNAs are involved in a variety of cellular functions. In particular, an increasing number of studies have revealed the functions of long noncoding RNA in various cancers; however, their precise roles and mechanisms of action remain to be elucidated. NORAD, a cytoplasmic long noncoding RNA, is upregulated by irradiation and functions as a potential oncogenic factor by binding and inhibiting Pumilio proteins (PUM1/PUM2). Here, we show that NORAD upregulates transforming growth facto ...[more]

PMID: 29722104

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Project description:BackgroundPancreatic cancer, one of the top two most fatal cancers, is characterized by a desmoplastic reaction that creates a dense microenvironment, promoting hypoxia and inducing the epithelial-to-mesenchymal transition (EMT) to facilitate invasion and metastasis. Recent evidence indicates that the long noncoding RNA NORAD may be a potential oncogenic gene and that this lncRNA is significantly upregulated during hypoxia. However, the overall biological role and clinical significance of NORAD remains largely unknown.MethodsNORAD expression was measured in 33 paired cancerous and noncancerous tissue samples by real-time PCR. The effects of NORAD on pancreatic cancer cells were studied by overexpression and knockdown in vitro. Insights into the mechanism of competitive endogenous RNAs (ceRNAs) were gained from bioinformatics analyses and luciferase assays. In vivo, metastatic potential was identified using an orthotopic model of PDAC and quantified using bioluminescent signals. Alterations in RhoA expression and EMT levels were identified and verified by immunohistochemistry and Western blotting.ResultsNORAD is highly expressed in pancreatic cancer tissues and upregulated in hypoxic conditions. NORAD upregulation is correlated with shorter overall survival in pancreatic cancer patients. Furthermore, NORAD overexpression promoted the migration and invasion of pancreatic carcinoma cells, while NORAD depletion inhibited EMT and metastasis in vitro and in vivo. In particular, NORAD may function as a ceRNA to regulate the expression of the small GTP binding protein RhoA through competition for hsa-miR-125a-3p, thereby promoting EMT.ConclusionsElevated expression of NORAD in pancreatic cancer tissues is linked to poor prognosis and may confer a malignant phenotype upon tumor cells. NORAD may function as a ceRNA to regulate the expression of the small GTP binding protein RhoA through competition for hsa-miR-125a-3p. This finding may contribute to a better understanding of the role played by lncRNAs in hypoxia-induced EMT and provide a potential novel diagnostic and therapeutic target for pancreatic cancer.

Dataset Information

Long noncoding RNA NORAD regulates transforming growth factor-? signaling and epithelial-to-mesenchymal transition-like phenotype.

Publications

Long noncoding RNA NORAD regulates transforming growth factor-β signaling and epithelial-to-mesenchymal transition-like phenotype.

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