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.

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Acknowledgements

This research was supported by the Recruitment Program of Global Youth Experts (C. Wu), grants (91229126 to D.L. and 81490753 to W.T.) from the National Natural Science Foundation of China, a grant (2014AA020609) from the National High-Tech Research and Development Program of China (C. Wu) and the Chinese Academy of Medical Sciences Intramural Funds (C. Wu, X.C. and J.Z.).

Author information

Author notes

    • Jian Zheng
    •  & Xudong Huang

    These authors contributed equally to this work.

Affiliations

  1. State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Jian Zheng
    • , Xudong Huang
    • , Zhongli Du
    • , Jiang Chang
    • , Lixuan Wei
    • , Yaling Han
    •  & Chen Wu
  2. Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Wen Tan
    • , Dianke Yu
    •  & Dongxin Lin
  3. Department of Abdominal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Chengfeng Wang
    •  & Xu Che
  4. Department of Genetics, Medical College of Soochow University, Suzhou, China.

    • Yifeng Zhou
  5. School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.

    • Xiaoping Miao
  6. Department of Radiation Oncology, Cancer Hospital, Fudan University, Shanghai, China.

    • Guoliang Jiang
  7. Department of Pancreas and Hepatobiliary Surgery, Cancer Hospital, Fudan University, Shanghai, China.

    • Xianjun Yu
  8. Department of Pathology, Shengjing Hospital, China Medical University, Shenyang, China.

    • Xianghong Yang
  9. Department of Epidemiology, Second Military Medical University, Shanghai, China.

    • Guangwen Cao
  10. Department of Gastroduodenal and Pancreatic Surgery, Hunan Province Tumor Hospital, Changsha, China.

    • Chaohui Zuo
  11. Department of Gastroenterology, First Affiliated Hospital, Second Military Medical University, Shanghai, China.

    • Zhaoshen Li
  12. Union Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.

    • Chunyou Wang
  13. Department of Surgery, University of Hong Kong, Hong Kong, China.

    • Siu Tim Cheung
  14. Department of Pathology, Affiliated Hospital, Inner Mongolia School of Medicine, Huhhot, China.

    • Yongfeng Jia
  15. Department of Pathology, Fujian Provincial Cancer Hospital, Fuzhou, China.

    • Xiongwei Zheng
  16. Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, Nanjing, China.

    • Hongbing Shen
  17. Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

    • Dongxin Lin

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Contributions

D.L. conceptualized and supervised this study. C. Wu, J.Z. and X.H. contributed to the study design. C. Wu and W.T. supervised the genome-wide association analysis. J.Z. and X.H. performed and analyzed the data from most functional assays. D.Y., J.C., Z.D., L.W. and Y.H. performed sample preparation, genotyping assays and association analysis. Chengfeng Wang, X.C., Y.Z., X.M., G.J., X. Yu, X. Yang, G.C., C.Z., Z.L., Chunyou Wang, S.T.C., Y.J., X.Z. and H.S. contributed human data and samples. D.L., J.Z. and C. Wu were involved in manuscript preparation.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Chen Wu or Dongxin Lin.

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    Supplementary Text and Figures

    Supplementary Figures 1–11 and Supplementary Tables 1–9.

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    Supplementary Data 1

    Genotyping data for rs11655237 in replication III samples.

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    Supplementary Data 2

    Quantification overview (111 proteins).

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    Supplementary Data 3

    Quantification overview (34 proteins).

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https://doi.org/10.1038/ng.3568

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