title: Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation.
abstract: 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.
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Tan
authors.affiliation: Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Dianke
authors.initials: D
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Zhongli
authors.initials: Z
authors.lastname: Du
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Chang
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Lixuan
authors.initials: L
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Abdominal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Chengfeng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Abdominal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Che
authors.affiliation: Department of Genetics, Medical College of Soochow University, Suzhou, China.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Miao
authors.affiliation: Department of Radiation Oncology, Cancer Hospital, Fudan University, Shanghai, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Department of Pancreas and Hepatobiliary Surgery, Cancer Hospital, Fudan University, Shanghai, China.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Pathology, Shengjing Hospital, China Medical University, Shenyang, China.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Epidemiology, Second Military Medical University, Shanghai, China.
authors.forename: Guangwen
authors.initials: G
authors.lastname: Cao
authors.affiliation: Department of Gastroduodenal and Pancreatic Surgery, Hunan Province Tumor Hospital, Changsha, China.
authors.forename: Chaohui
authors.initials: C
authors.lastname: Zuo
authors.affiliation: Department of Gastroenterology, First Affiliated Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Zhaoshen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Union Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.
authors.forename: Chunyou
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Hong Kong, Hong Kong, China.
authors.forename: Siu Tim
authors.initials: ST
authors.lastname: Cheung
authors.affiliation: Department of Pathology, Affiliated Hospital, Inner Mongolia School of Medicine, Huhhot, China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Pathology, Fujian Provincial Cancer Hospital, Fuzhou, China.
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, Nanjing, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.|Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Dongxin
authors.initials: D
authors.lastname: Lin
mesh_terms: D001665:Binding Sites; D016022:Case-Control Studies; D049109:Cell Proliferation; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D000072260:RNA Splicing Factors / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C576014:MIRN1231 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D000072260:RNA Splicing Factors; D062085:RNA, Long Noncoding; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D045643:DNA Repair Enzymes; C417041:PRPF19 protein, human