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

// Xiang Li 1, * , Shi-jiang Deng 1, * , Shuai Zhu 1 , Yan Jin 1 , Shi-peng Cui 1 , Jing-yuan Chen 1 , Cheng Xiang 1 , Qun-ying Li 2 , Chi He 1 , Shu-feng Zhao 1 , Heng-yu Chen 1 , Yi Niu 1 , Yang Liu 1 , Shi-chang Deng 1 , Chun-you Wang 1 , Gang Zhao 1 1 Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 2 Department of Medical Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China * These authors contributed equally to this work Correspondence to: Gang Zhao, e-mail: gangzhao@aliyun.com Chun-you Wang, e-mail: chunyouwang52@163.com Keywords: HIF-1α, lncRNAs, miRNAs, KRAS, pancreatic cancer Received: April 22, 2015 Accepted: December 26, 2015 Published: January 07, 2016 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.