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Abstract
Recent studies indicate that long non-coding RNAs (lncRNAs) play crucial roles in numerous cancers, while their function in pancreatic cancer is rarely elucidated. The present study identifies a functional lncRNA and its potential role in tumorigenesis of pancreatic cancer. Microarray co-assay for lncRNAs and mRNAs demonstrates that lncRNA-NUTF2P3-001 is remarkably overexpressed in pancreatic cancer and chronic pancreatitis tissues, which positively correlates with KRAS mRNA expression. After downregulating lncRNA-NUTF2P3-001, the proliferation and invasion of pancreatic cancer cell are significantly inhibited both in vitro and vivo, accompanying with decreased KRAS expression. The dual-luciferase reporter assay further validates that lncRNA-NUTF2P3-001 and 3′UTR of KRAS mRNA competitively bind with miR-3923. Furthermore, miR-3923 overexpression simulates the inhibiting effects of lncRNA-NUTF2P3-001-siRNA on pancreatic cancer cell, which is rescued by miR-3923 inhibitor. Specifically, the present study further reveals that lncRNA-NUTF2P3-001 is upregulated in pancreatic cancer cells under hypoxia and CoCl2 treatment, which is attributed to the binding of hypoxia-inducible factor-1α (HIF-1α) to hypoxia response elements (HREs) in the upstream of KRAS promoter. Data from pancreatic cancer patients show a positive correlation between lncRNA-NUTF2P3-001 and KRAS, which is associated with advanced tumor stage and worse prognosis. Hence, our data provide a new lncRNA-mediated regulatory mechanism for the tumor oncogene KRAS and implicate that lncRNA-NUTF2P3-001 and miR-3923 can be applied as novel predictors and therapeutic targets for pancreatic cancer.
Highlights
The long non-coding RNAs are a class of non-coding RNAs with more than 200 nucleotides in length [1], which account for the vast majority of transcripts in human genome compared with the protein-coding RNAs [2, 3]
LncRNA-NUTF2P3-001 is overexpressed in pancreatic cancer and chronic pancreatitis tissues, which positively correlates with KRAS expression and clinical outcome of pancreatic cancer patients
Data of CNC network implied that long non-coding RNAs (lncRNAs)-NUTF2P3-001 significantly correlated with the expression of KRAS mRNA (Figure 1A right), which was upregulated in pancreatic cancer (PC) and chronic pancreatitis (CP) (Figure 1A left)
Summary
The long non-coding RNAs (lncRNAs) are a class of non-coding RNAs with more than 200 nucleotides in length [1], which account for the vast majority of transcripts in human genome compared with the protein-coding RNAs [2, 3]. Yang et al revealed that lncRNA-HNF1A-AS1 was highly expressed in oesophageal adenocarcinoma and promoted cell invasion and growth by modulation of chromatin and nucleosome assembly as well as by H19 induction [6]. The other researches demonstrated that lncRNA-HOTTIP/HOXA13 and lncRNA-HEIH participated in the modulation of liver cancer cell metastasis and progression [7, 8]. Data demonstrates that some differentially regulated lncRNAs are correlated with prognosis in patients with pancreatic cancer [9,10,11,12]. Since KRAS is widely considered as promoter in pancreatic cancer tumorigenesis [15], we speculate that lncRNA-NUTF2P3-001 might be a functional lncRNA in pancreatic cancer by regulating KRAS expression
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