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Lipocalin-2 inhibits pancreatic cancer stemness via the AKT/c-Jun pathway

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Abstract

Cancer stem cells (CSCs) are involved in cancer recurrence and metastasis owing to their self-renewal properties and drug-resistance capacity. Lipocalin-2 (Lcn2) of the lipocalin superfamily is highly expressed in pancreatic cancer. Nevertheless, reports on the involvement of Lcn2 in the regulation of pancreatic CSC properties are scant. This study is purposed to investigate whether Lcn2 plays a crucial role in CSC renewal and stemness maintenance in pancreatic carcinoma. Immunohistochemistry results of tumor tissue chips together with Gene Expression Omnibus sequencing files confirmed that Lcn2 is highly expressed in pancreatic carcinoma compared with that in normal tissues. The exogenous expression of Lcn2 attenuated CSC-associated SOX2, CD44, and EpCAM expression and suppressed sarcosphere formation and tumorigenesis in the pancreatic carcinoma cell line PANC-1, which showed low expression of Lcn2. However, Lcn2 knockout in BxPC-3 cell line, which presented high Lcn2 expression, promoted CSC stemness, further enhancing sarcosphere formation and tumorigenesis. Moreover, Lcn2 was found to regulate stemness in pancreatic cancer depending on the activation of AKT and c-Jun. Lcn2 suppresses stemness properties in pancreatic carcinoma by activating the AKT-c-Jun pathway, and thus, it may be a novel candidate to suppress the stemness of pancreatic cancer. This study provides a new insight into disease progression.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank Mrs. Tianyu Dong (Research Center for Instrumental Analysis, Hebei Medical University) for her excellent technical assistance. This work was supported by Hebei Medical University, Natural Science Foundation of Hebei Province (H2020206524); Overseas Researcher Program in Hebei Provincial Department of Human Resources and Social Security (C20190352); National Natural Science Foundation of China (81602579); and “Chun yu” Fund of Hebei Medical University (CYYQ201901).

Funding

This work was supported by Hebei Medical University, Natural Science Foundation of Hebei Province (Grant number H2020206524); Overseas Researcher Program in Hebei Provincial Department of Human Resources and Social Security (Grant number C20190352); National Natural Science Foundation of China (Grant number 81602579); and “Chun yu” Fund of Hebei Medical University (Grant number CYYQ201901).

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Author notes

  1. Peipei Hao and Jiamin Zhang contributed equally.

Authors and Affiliations

  1. Department of Human Anatomy, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China

    Peipei Hao, Jiamin Zhang, Shu Fang, Miaomiao Jia, Qian Ren & Huixian Cui

  2. International Cooperation Laboratory of Stem Cell Research, Shijiazhuang, Hebei, China

    Peipei Hao, Jiamin Zhang, Shu Fang, Miaomiao Jia, Xian Xian, Qian Ren, Fengming Yue & Huixian Cui

  3. Department of Pathogenic Biology, Hebei Medical University, Shijiazhuang, Hebei, China

    Xian Xian

  4. Department of Otorhinolaryngology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

    Sinan Yan

  5. Department of General Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

    Yunpeng Wang

  6. Department of Histology and Embryology, Shinshu University School of Medicine, Matsumoto, Nagano, 390-0312, Japan

    Fengming Yue

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  1. Peipei Hao
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Contributions

All authors contributed to the study conception and design. Material preparation, and data collection and analysis were performed by SF, MJ, XX, SY, YW, QR. The first draft of the manuscript was written by PH, JZ, FY, HC. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Fengming Yue or Huixian Cui.

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The experiments in this article was approved by the Laboratory Animal Ethical and Welfare Committee of Hebei Medical University (IACUC-Hebmu-2022008).

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Hao, P., Zhang, J., Fang, S. et al. Lipocalin-2 inhibits pancreatic cancer stemness via the AKT/c-Jun pathway. Human Cell 35, 1475–1486 (2022). https://doi.org/10.1007/s13577-022-00735-z

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