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

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

doi:10.1038/ng.3568

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

Nat Genet. 2016 Jul;48(7):747-57. doi: 10.1038/ng.3568. Epub 2016 May 23.

Authors

Jian Zheng¹, Xudong Huang¹, Wen Tan², Dianke Yu², Zhongli Du¹, Jiang Chang¹, Lixuan Wei¹, Yaling Han¹, Chengfeng Wang³, Xu Che³, Yifeng Zhou⁴, Xiaoping Miao⁵, Guoliang Jiang⁶, Xianjun Yu⁷, Xianghong Yang⁸, Guangwen Cao⁹, Chaohui Zuo¹⁰, Zhaoshen Li¹¹, Chunyou Wang¹², Siu Tim Cheung¹³, Yongfeng Jia¹⁴, Xiongwei Zheng¹⁵, Hongbing Shen¹⁶, Chen Wu¹, Dongxin Lin^{2

17}

Affiliations

¹ State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
³ Department of Abdominal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁴ Department of Genetics, Medical College of Soochow University, Suzhou, China.
⁵ School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.
⁶ Department of Radiation Oncology, Cancer Hospital, Fudan University, Shanghai, China.
⁷ Department of Pancreas and Hepatobiliary Surgery, Cancer Hospital, Fudan University, Shanghai, China.
⁸ Department of Pathology, Shengjing Hospital, China Medical University, Shenyang, China.
⁹ Department of Epidemiology, Second Military Medical University, Shanghai, China.
¹⁰ Department of Gastroduodenal and Pancreatic Surgery, Hunan Province Tumor Hospital, Changsha, China.
¹¹ Department of Gastroenterology, First Affiliated Hospital, Second Military Medical University, Shanghai, China.
¹² Union Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.
¹³ Department of Surgery, University of Hong Kong, Hong Kong, China.
¹⁴ Department of Pathology, Affiliated Hospital, Inner Mongolia School of Medicine, Huhhot, China.
¹⁵ Department of Pathology, Fujian Provincial Cancer Hospital, Fuzhou, China.
¹⁶ Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, Nanjing, China.
¹⁷ Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

PMID: 27213290
DOI: 10.1038/ng.3568

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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Case-Control Studies
Cell Proliferation
DNA Repair Enzymes / genetics
DNA Repair Enzymes / metabolism
Extracellular Signal-Regulated MAP Kinases / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism
Gene Expression Regulation, Neoplastic
Genome-Wide Association Study
Humans
MicroRNAs / genetics*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Pancreas / metabolism
Pancreatic Neoplasms / genetics*
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology
Polymorphism, Single Nucleotide / genetics*
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
Proteolysis
RNA Splicing Factors / genetics
RNA Splicing Factors / metabolism
RNA, Long Noncoding / genetics*
STAT1 Transcription Factor / genetics
STAT1 Transcription Factor / metabolism
Signal Transduction
Ubiquitination
src-Family Kinases / genetics
src-Family Kinases / metabolism

Substances

MIRN1231 microRNA, human
MicroRNAs
Nuclear Proteins
RNA Splicing Factors
RNA, Long Noncoding
STAT1 Transcription Factor
STAT1 protein, human
src-Family Kinases
Extracellular Signal-Regulated MAP Kinases
PTPN11 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 11
DNA Repair Enzymes
PRPF19 protein, human