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

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

Author information

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.

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.

PMID:
27213290
DOI:
10.1038/ng.3568
[Indexed for MEDLINE]

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