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.


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


  • 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