Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation

• DOI: 10.1038/ng.3568
• Publication Date: 2016-05-24T13:21:18Z
• Authors: Jian Zheng; Xudong Huang; Wen Tan; Dianke Yu; Zhongli Du; Jiang Chang; Lixuan Wei; Yaling Han; Chengfeng Wang; Xu Che; Yifeng Zhou; Xiaoping Miao; Guoliang Jiang; Xianjun Yu; Xianghong Yang; Guangwen Cao; Chaohui Zuo; Zhaoshen Li; Chunyou Wang; Siu Tim Cheung; Yongfeng Jia; Xiongwei Zheng; Hongbing Shen; Chen Wu; Dongxin Lin
• Keywords: 0301 basic medicine; Binding Sites; Ubiquitination; Nuclear Proteins; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Polymorphism, Single Nucleotide; 3. Good health; Gene Expression Regulation, Neoplastic; Pancreatic Neoplasms; MicroRNAs; 03 medical and health sciences; DNA Repair Enzymes; STAT1 Transcription Factor; Case-Control Studies; Proteolysis; Humans; RNA, Long Noncoding; RNA Splicing Factors; Extracellular Signal-Regulated MAP Kinases; Pancreas; Cell Proliferation; Genome-Wide Association Study; Signal Transduction

Genome-wide association studies have identified several loci associated with pancreatic cancer risk; however, the mechanisms by which genetic factors influence the development of sporadic pancreatic cancer remain largely unknown. Here, by using genome-wide association analysis and functional characterization, we identify a long intergenic noncoding RNA (lincRNA), LINC00673, as a potential tumor suppressor whose germline variation is associated with pancreatic cancer risk. LINC00673 is able to reinforce the interaction of PTPN11 with PRPF19, an E3 ubiquitin ligase, and promote PTPN11 degradation through ubiquitination, which causes diminished SRC-ERK oncogenic signaling and enhanced activation of the STAT1-dependent antitumor response. A G>A change at rs11655237 in exon 4 of LINC00673 creates a target site for miR-1231 binding, which diminishes the effect of LINC00673 in an allele-specific manner and thus confers susceptibility to tumorigenesis. These findings shed new light on the important role of LINC00673 in maintaining cell homeostasis and how its germline variation might confer susceptibility to pancreatic cancer.