Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer

  1. Lili Liao
  2. Zongzhi Z Liu
  3. Lauren Langbein
  4. Weijia Cai
  5. Eun-Ah Cho
  6. Jie Na
  7. Xiaohua Niu
  8. Wei Jiang
  9. Zhijiu Zhong
  10. Wesley L Cai
  11. Geetha Jagannathan
  12. Essel Dulaimi
  13. Joseph R Testa
  14. Robert G Uzzo
  15. Yuxin Wang
  16. George R Stark
  17. Jianxin Sun
  18. Stephen C Peiper
  19. Yaomin Xu  Is a corresponding author
  20. Qin Yan  Is a corresponding author
  21. Haifeng Yang  Is a corresponding author
  1. Thomas Jefferson University, United States
  2. Yale University, United States
  3. Mayo Clinic, United States
  4. The Sixth Affiliated Hospital of Guangzhou Medical University, China
  5. Fox Chase Cancer Center, United States
  6. Lerner Research Institute, Cleveland Clinic, United States
  7. Vanderbilt University, United States

Abstract

Whereas VHL inactivation is a primary event in clear cell renal cell carcinoma (ccRCC), the precise mechanism(s) of how this interacts with the secondary mutations in tumor suppressor genes, including PBRM1, KDM5C/JARID1C, SETD2, and/orBAP1, remains unclear. Gene expression analyses reveal that VHL, PBRM1, or KDM5C share a common regulation of interferon response expression signature. Loss of HIF2a, PBRM1, or KDM5C in VHL-/-cells reduces the expression of interferon stimulated gene factor 3 (ISGF3), a transcription factor that regulates the interferon signature. Moreover, loss of SETD2 or BAP1 also reduces the ISGF3 level. Finally, ISGF3 is strongly tumor-suppressive in a xenograft model as its loss significantly enhances tumor growth. Conversely, reactivation of ISGF3 retards tumor growth by PBRM1-deficient ccRCC cells. Thus after VHL inactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in ccRCC.

Data availability

Microarray data have been deposited inn GEO under the accession code GSE108229.

The following data sets were generated

Article and author information

Author details

  1. Lili Liao

    Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Zongzhi Z Liu

    Department of Pathology, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Lauren Langbein

    Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3007-5287
  4. Weijia Cai

    Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Eun-Ah Cho

    Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jie Na

    Department of Health Sciences Research, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Xiaohua Niu

    Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Wei Jiang

    Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Zhijiu Zhong

    Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Wesley L Cai

    Department of Pathology, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Geetha Jagannathan

    Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Essel Dulaimi

    Fox Chase Cancer Center, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Joseph R Testa

    Fox Chase Cancer Center, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Robert G Uzzo

    Fox Chase Cancer Center, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Yuxin Wang

    Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. George R Stark

    Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Jianxin Sun

    Department of Medicine, Thomas Jefferson University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Stephen C Peiper

    Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Yaomin Xu

    Department of Biostatistics, Vanderbilt University, Nashville, United States
    For correspondence
    yaomin.xu@vanderbilt.edu
    Competing interests
    The authors declare that no competing interests exist.
  20. Qin Yan

    Department of Pathology, Yale University, New Haven, United States
    For correspondence
    qin.yan@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4077-453X
  21. Haifeng Yang

    Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, United States
    For correspondence
    Haifeng.yang@jefferson.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0892-9055

Funding

National Cancer Institute (R01 CA155015)

  • Haifeng Yang

National Cancer Institute (P30CA056036)

  • Haifeng Yang

Department of Defence (W81XWH-16-1-0326)

  • Qin Yan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were conducted in accordance with protocol 01462-935A approved by the IACUC of Thomas Jefferson University and protocol 2015-11286 approved by the IACUC of Yale University.

Copyright

© 2018, Liao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Lili Liao
  2. Zongzhi Z Liu
  3. Lauren Langbein
  4. Weijia Cai
  5. Eun-Ah Cho
  6. Jie Na
  7. Xiaohua Niu
  8. Wei Jiang
  9. Zhijiu Zhong
  10. Wesley L Cai
  11. Geetha Jagannathan
  12. Essel Dulaimi
  13. Joseph R Testa
  14. Robert G Uzzo
  15. Yuxin Wang
  16. George R Stark
  17. Jianxin Sun
  18. Stephen C Peiper
  19. Yaomin Xu
  20. Qin Yan
  21. Haifeng Yang
(2018)
Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer
eLife 7:e37925.
https://doi.org/10.7554/eLife.37925

Share this article

https://doi.org/10.7554/eLife.37925

Further reading

    1. Cancer Biology
    Yang Peng, Jing Yang ... Liang Weng
    Research Article

    Background:

    Cervical adenocarcinoma (ADC) is more aggressive compared to other types of cervical cancer (CC), such as squamous cell carcinoma (SCC). The tumor immune microenvironment (TIME) and tumor heterogeneity are recognized as pivotal factors in cancer progression and therapy. However, the disparities in TIME and heterogeneity between ADC and SCC are poorly understood.

    Methods:

    We performed single-cell RNA sequencing on 11 samples of ADC tumor tissues, with other 4 SCC samples served as controls. The immunochemistry and multiplexed immunofluorescence were conducted to validate our findings.

    Results:

    Compared to SCC, ADC exhibited unique enrichments in several sub-clusters of epithelial cells with elevated stemness and hyper-malignant features, including the Epi_10_CYSTM1 cluster. ADC displayed a highly immunosuppressive environment characterized by the enrichment of regulatory T cells (Tregs) and tumor-promoting neutrophils. The Epi_10_CYSTM1 cluster recruits Tregs via ALCAM-CD6 signaling, while Tregs reciprocally induce stemness in the Epi_10_CYSTM1 cluster through TGFβ signaling. Importantly, our study revealed that the Epi_10_CYSTM1 cluster could serve as a valuable predictor of lymph node metastasis for CC patients.

    Conclusions:

    This study highlights the significance of ADC-specific cell clusters in establishing a highly immunosuppressive microenvironment, ultimately contributing to the heightened aggressiveness and poorer prognosis of ADC compared to SCC.

    Funding:

    Funded by the National Natural Science Foundation of China (82002753; 82072882; 81500475) and the Natural Science Foundation of Hunan Province (2021JJ40324; 2022JJ70103).