Association of human breast cancer CD44-/CD24- cells with delayed distant metastasis

  1. Xinbo Qiao
  2. Yixiao Zhang
  3. Lisha Sun
  4. Qingtian Ma
  5. Jie Yang
  6. Liping Ai
  7. Jinqi Xue
  8. Guanglei Chen
  9. Hao Zhang
  10. Ce Ji
  11. Xi Gu
  12. Haixin Lei
  13. Yongliang Yang
  14. Caigang Liu  Is a corresponding author
  1. Shengjing Hospital of China Medical University, China
  2. Shengjing hospital of China Medical University, China
  3. Tongji Medical College, China
  4. Xijing Hospital of Fourth Military Medical University, China
  5. Cancer Hospital of China Medical University, China
  6. Cancer Center of Dalian Medical University, China
  7. Dalian University of Technology, China

Abstract

Tumor metastasis remains the main cause of breast cancer-related deaths, especially delayed breast cancer distant metastasis. The current study assessed the frequency of CD44-/CD24- breast cancer cells in 576 tissue specimens for associations with clinicopathological features and metastasis and investigated the underlying molecular mechanisms. The results indicated that higher frequency (≥19.5%) of CD44-/CD24- cells was associated with delayed postoperative breast cancer metastasis. Furthermore, CD44-/CD24- triple negative breast cancer (TNBC) cells spontaneously converted into CD44+/CD24- cancer stem cells (CSCs) with properties similar to CD44+/CD24- CSCs from primary human breast cancer cells and parental TNBC cells in terms of stemness marker expression, self-renewal, differentiation, tumorigenicity and lung metastasis in vitro and in NOD/SCID mice. RNA sequencing identified several differentially expressed genes (DEGs) in newly converted CSCs and RHBDL2, one of the DEGs, expression was up-regulated. More importantly, RHBDL2 silencing inhibited the YAP1/USP31/NF-κB signaling and attenuated spontaneous CD44-/CD24- cell conversion into CSCs and their mammosphere formation. These findings suggest that the frequency of CD44-/CD24- tumor cells and RHBDL2 may be valuable for prognosis of delayed breast cancer metastasis, particularly for TNBC.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Xinbo Qiao

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  2. Yixiao Zhang

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  3. Lisha Sun

    Department of Oncology, Cancer Stem Cell and Translational Medicine Laboratory, Shengjing hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  4. Qingtian Ma

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  5. Jie Yang

    Tongji Medical College of HUST, Tongji Medical College, Wuhan, China
    Competing interests
    No competing interests declared.
  6. Liping Ai

    Department of Clinical Oncology, Xijing Hospital of Fourth Military Medical University, Xi'an, China
    Competing interests
    No competing interests declared.
  7. Jinqi Xue

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  8. Guanglei Chen

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  9. Hao Zhang

    Department of Breast Surgery, Cancer Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  10. Ce Ji

    Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  11. Xi Gu

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  12. Haixin Lei

    Institute of Cancer Stem Cell, Cancer Center of Dalian Medical University, Dalian, China
    Competing interests
    No competing interests declared.
  13. Yongliang Yang

    Center for Molecular Medicine, School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China
    Competing interests
    No competing interests declared.
  14. Caigang Liu

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    For correspondence
    angel-s205@163.com
    Competing interests
    Caigang Liu, Reviewing Editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2083-235X

Funding

Foundation for Innovative Research Groups of the National Natural Science Foundation of China (#81572609)

  • Caigang Liu

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

Ethics

Animal experimentation: The experimental protocol was approved by the Animal Research and Care Committee of China Medical University (Shenyang, China) and followed the Guidelines of the Care and Use of Laboratory Animals issued by the Chinese Council on Animal Research. Female BALB/c nude mice (6 weeks old) were obtained from Human Silaikejingda Laboratory Animals (Changsha, China) and housed in a specific pathogen-free facility with free access to autoclaved food and water. All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering. The current study was approved by the Ethics Committee of all three hospital review board review boards ((Project identification code: Project identification code: 2018PS304K, date on 03/05/2018 2018PS304K, date on 03/05/2018))

Reviewing Editor

  1. Renata Pasqualini, Rutgers University, United States

Publication history

  1. Received: December 3, 2020
  2. Accepted: July 25, 2021
  3. Accepted Manuscript published: July 28, 2021 (version 1)
  4. Version of Record published: August 6, 2021 (version 2)

Copyright

© 2021, Qiao 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. Xinbo Qiao
  2. Yixiao Zhang
  3. Lisha Sun
  4. Qingtian Ma
  5. Jie Yang
  6. Liping Ai
  7. Jinqi Xue
  8. Guanglei Chen
  9. Hao Zhang
  10. Ce Ji
  11. Xi Gu
  12. Haixin Lei
  13. Yongliang Yang
  14. Caigang Liu
(2021)
Association of human breast cancer CD44-/CD24- cells with delayed distant metastasis
eLife 10:e65418.
https://doi.org/10.7554/eLife.65418

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