Hypoxia-induced lncRNA-NUTF2P3-001 contributes to tumorigenesis of pancreatic cancer by derepressing the miR-3923/KRAS pathway

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.

Reciprocal loop of hypoxia‐inducible factor‐1α (HIF‐1α) and metastasis‐associated protein 2 (MTA2) contributes to the progression of pancreatic carcinoma by suppressing E‐cadherin transcription

“…Multivariate analysis showed that a high MTA2 protein level was an independent prognostic factor for lower overall survival of pancreatic carcinoma patients [18]. MTA2 was correlated with tumour invasion and tumour embolus formation in gastric carcinoma, and trapping MTA2 in the cytosol or knockdown of MTA2 inhibited growth and metastasis [28]. MTA2 is an independent prognostic factor for the survival of colorectal carcinoma patients, and high MTA2 expression correlated with poor overall survival [29].…”

Long noncoding RNA HAS2‐AS1 mediates hypoxia‐induced invasiveness of oral squamous cell carcinoma

“…Dysregulated lncRNAs expression in cancer tissues correlates with the spectrum of disease progression and may be regarded as a predictor of patient outcomes . Recently, several lncRNAs have been reported to participate in hypoxia‐associated cancer biology, implying a potential role of lncRNA in maintaining cellular homeostasis and enabling adaptive survival under hypoxia . Mineo et al identified hypoxia‐inducible factor 1 alpha‐antisense RNA 2 (HIF1A‐AS2) as a subtype specific hypoxia‐inducible lncRNA, up‐regulated in mesenchymal glioblastoma multiforme stem‐like cells.…”

“…17,18 Recently, several lncRNAs have been reported to participate in hypoxiaassociated cancer biology, implying a potential role of lncRNA in maintaining cellular homeostasis and enabling adaptive survival under hypoxia. [19][20][21][22] Mineo et al 23 identified hypoxia-inducible factor 1 alphaantisense RNA 2 (HIF1A-AS2) as a subtype specific hypoxia-inducible lncRNA, up-regulated in mesenchymal glioblastoma multiforme stemlike cells. Deregulation of HIF1A-AS2 interferes with cell growth, self-renewal, and hypoxia-dependent molecular reprogramming.…”

Long non-coding RNA CUDR promotes malignant phenotypes in pancreatic ductal adenocarcinoma via activating AKT and ERK signaling pathways

“…Increasing evidence has suggested that long non-coding RNAs (lncRNAs) serve multiple functions in tumor initiation and development, and represent novel targets for cancer diagnosis and therapies (5,6). Several lncRNAs have been associated with pancreatic cancer and may be used as biomarkers of PDAC (7)(8)(9).…”