The chemokine CXCL13 in lung cancers associated with environmental polycyclic aromatic hydrocarbons pollution

  1. Gui-Zhen Wang
  2. Xin Cheng
  3. Bo Zhou
  4. Zhe-Sheng Wen
  5. Yun-Chao Huang
  6. Hao-Bin Chen
  7. Gao-Feng Li
  8. Zhi-Liang Huang
  9. Yong-Chun Zhou
  10. Lin Feng
  11. Ming-Ming Wei
  12. Li-Wei Qu
  13. Yi Cao
  14. Guang-Biao Zhou  Is a corresponding author
  1. University of Chinese Academy of Sciences, China
  2. Sun Yat-Sen University, China
  3. Kunming Medical University, China
  4. The First People's Hospital of Qujing, China
  5. The People's Liberation Army General Hospital, China
  6. Chinese Academy of Sciences, China

Abstract

More than 90% of lung cancers are caused by cigarette smoke and air pollution, with polycyclic aromatic hydrocarbons (PAHs) as key carcinogens. In Xuanwei City of Yunnan Province the lung cancer incidence is among the highest in China attributed to smoky coal combustion-generated PAH pollution. Here we screened for abnormal inflammatory factors in non-small cell lung cancers (NSCLCs) from Xuanwei and control regions (CR) where smoky coal was not used, and found that a chemokine CXCL13 was overexpressed in 63/70 (90%) of Xuanwei NSCLCs and 44/71 (62%) of smoker and 27/60 (45%) of non-smoker CR patients. CXCL13 overexpression was associated with the region Xuanwei and cigarette smoke. The key carcinogen bezo(a)pyrene (BaP) induced CXCL13 production in lung epithelial cells and in mice prior to development of detectable lung cancer. Deficiency in cxcl13 or its receptor, cxcr5, abrogated BaP-induced lung cancer in mice, demonstrating CXCL13's critical role in PAH-induced lung carcinogenesis.

Article and author information

Author details

  1. Gui-Zhen Wang

    State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Xin Cheng

    State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Bo Zhou

    State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Zhe-Sheng Wen

    Department of Thoracic Surgery, Cancer Center, Sun Yat-Sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Yun-Chao Huang

    Department of Thoracic Surgery, Yunnan Tumor Hospital, Kunming Medical University, Kunming, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Hao-Bin Chen

    Department of Pathology, The First People's Hospital of Qujing, Qujing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Gao-Feng Li

    Department of Thoracic Surgery, Yunnan Tumor Hospital, Kunming Medical University, Kunming, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Zhi-Liang Huang

    Department of Thoracic Surgery, Cancer Center, Sun Yat-Sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Yong-Chun Zhou

    Department of Thoracic Surgery, Yunnan Tumor Hospital, Kunming Medical University, Kunming, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Lin Feng

    Department of Pathology, The People's Liberation Army General Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Ming-Ming Wei

    State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Li-Wei Qu

    State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Yi Cao

    Laboratory of Molecular and Experimental Pathology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Guang-Biao Zhou

    State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Beijing, China
    For correspondence
    gbzhou@ioz.ac.cn
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: Animal studies were conducted according to protocols approved by the Animal Ethics Committee of the Institute of Zoology, Chinese Academy of Sciences, with the approval ID of AEC2010070202.

Human subjects: The study was approved by the local research ethics committees of all participating sites; all lung cancer samples were collected with informed consent.

Copyright

© 2015, Wang 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.

Metrics

  • 3,593
    views
  • 839
    downloads
  • 69
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Gui-Zhen Wang
  2. Xin Cheng
  3. Bo Zhou
  4. Zhe-Sheng Wen
  5. Yun-Chao Huang
  6. Hao-Bin Chen
  7. Gao-Feng Li
  8. Zhi-Liang Huang
  9. Yong-Chun Zhou
  10. Lin Feng
  11. Ming-Ming Wei
  12. Li-Wei Qu
  13. Yi Cao
  14. Guang-Biao Zhou
(2015)
The chemokine CXCL13 in lung cancers associated with environmental polycyclic aromatic hydrocarbons pollution
eLife 4:e09419.
https://doi.org/10.7554/eLife.09419

Share this article

https://doi.org/10.7554/eLife.09419

Further reading

    1. Cancer Biology
    Ismail M Meraz, Mourad Majidi ... Jack A Roth
    Research Article

    Expression of NPRL2/TUSC4, a tumor-suppressor gene, is reduced in many cancers including NSCLC. Restoration of NPRL2 induces DNA damage, apoptosis, and cell-cycle arrest. We investigated NPRL2 antitumor immune responses in aPD1R/KRAS/STK11mt NSCLC in humanized-mice. Humanized-mice were generated by transplanting fresh human cord blood-derived CD34 stem cells into sub-lethally irradiated NSG mice. Lung-metastases were developed from KRAS/STK11mt/aPD1R A549 cells and treated with NPRL2 w/wo pembrolizumab. NPRL2-treatment reduced lung metastases significantly, whereas pembrolizumab was ineffective. Antitumor effect was greater in humanized than non-humanized-mice. NPRL2 + pembrolizumab was not synergistic in KRAS/STK11mt/aPD1R tumors but was synergistic in KRASwt/aPD1S H1299. NPRL2 also showed a significant antitumor effect on KRASmt/aPD1R LLC2 syngeneic-tumors. The antitumor effect was correlated with increased infiltration of human cytotoxic-T, HLA-DR+DC, CD11c+DC, and downregulation of myeloid and regulatory-T cells in TME. Antitumor effect was abolished upon in-vivo depletion of CD8-T, macrophages, and CD4-T cells whereas remained unaffected upon NK-cell depletion. A distinctive protein-expression profile was found after NPRL2 treatment. IFNγ, CD8b, and TBX21 associated with T-cell functions were significantly increased, whereas FOXP3, TGFB1/B2, and IL-10RA were strongly inhibited by NPRL2. A list of T-cell co-inhibitory molecules was also downregulated. Restoration of NPRL2 exhibited significantly slower tumor growth in humanized-mice, which was associated with increased presence of human cytotoxic-T, and DC and decreased percentage of Treg, MDSC, and TAM in TME. NPRL2-stable cells showed a substantial increase in colony-formation inhibition and heightened sensitivity to carboplatin. Stable-expression of NPRL2 resulted in the downregulation of MAPK and AKT-mTOR signaling. Taken-together, NPRL2 gene-therapy induces antitumor activity on KRAS/STK11mt/aPD1R tumors through DC-mediated antigen-presentation and cytotoxic immune-cell activation.

    1. Biochemistry and Chemical Biology
    2. Cancer Biology
    Flavie Coquel, Sing-Zong Ho ... Philippe Pasero
    Research Article

    Cancer cells display high levels of oncogene-induced replication stress (RS) and rely on DNA damage checkpoint for viability. This feature is exploited by cancer therapies to either increase RS to unbearable levels or inhibit checkpoint kinases involved in the DNA damage response. Thus far, treatments that combine these two strategies have shown promise but also have severe adverse effects. To identify novel, better-tolerated anticancer combinations, we screened a collection of plant extracts and found two natural compounds from the plant, Psoralea corylifolia, that synergistically inhibit cancer cell proliferation. Bakuchiol inhibited DNA replication and activated the checkpoint kinase CHK1 by targeting DNA polymerases. Isobavachalcone interfered with DNA double-strand break repair by inhibiting the checkpoint kinase CHK2 and DNA end resection. The combination of bakuchiol and isobavachalcone synergistically inhibited cancer cell proliferation in vitro. Importantly, it also prevented tumor development in xenografted NOD/SCID mice. The synergistic effect of inhibiting DNA replication and CHK2 signaling identifies a vulnerability of cancer cells that might be exploited by using clinically approved inhibitors in novel combination therapies.