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Hypoxia promotes conversion to a stem cell phenotype in prostate cancer cells by activating HIF-1α/Notch1 signaling pathway

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Abstract

Purpose

The hypoxic tumor microenvironment and the maintenance of stem cells are relevant to the malignancy of prostate cancer (PCa). However, whether HIF-1α in the hypoxic microenvironment mediates the transformation of prostate cancer to a stem cell phenotype and the mechanism have not been elucidated.

Materials and methods

Prostate cancer stem cells (PCSCs) from PC-3 cell lines were examined for the expression of CD44, CD133, ALDH1, HIF-1α, Notch1, and HES1. We observed the effect of knockdown HIF-1α in vitro and mice models and evaluated the impact of HIF-1α on the Notch1 pathway as well as stem cell dedifferentiation. The effects on sphere formation, cell proliferation, apoptosis, cell cycle, and invasive metastasis were evaluated.

Results

In our study, hypoxia upregulated HIF-1α expression and induced a stem cell phenotype through activation of the Notch1 pathway, leading to enhanced proliferation, invasion, and migration of PCa PC-3 cells. The knockdown of HIF-1α significantly inhibited cell dedifferentiation and the ability to proliferate, invade and metastasize. However, the inhibitory effect of knocking down HIF-1α was reversed by Jagged1, an activator of the Notch1 pathway. These findings were further confirmed in vivo, where hypoxia could enhance the tumorigenicity of xenograft tumors by upregulating the expression of HIF-1α to activate the Notch1 pathway. In addition, the expression of HIF-1α and Notch1 was significantly increased in human PCa tissues, and high expression of HIF-1α correlated with the malignancy of PCa.

Conclusion

In a hypoxic environment, HIF-1α promotes PCa cell dedifferentiation to stem-like cell phenotypes by activating the Notch1 pathway and enhancing the proliferation and invasive capacity of PC-3 cells.

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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.

References

  1. Valle S, Sharifi N. Targeting Glucocorticoid Metabolism in Prostate Cancer. Endocrinology. 2021;162.

  2. Qiu H, Cao S, Xu R. Cancer incidence, mortality, and burden in China: a time-trend analysis and comparison with the United States and United Kingdom based on the global epidemiological data released in 2020. Cancer Commun (Lond). 2021;41:1037–48.

    Article  PubMed  Google Scholar 

  3. Netto GJ, Amin MB, Berney DM, Comperat EM, Gill AJ, Hartmann A, et al. The 2022 World health organization classification of tumors of the urinary system and male genital organs-part b: prostate and urinary tract tumors. Eur Urol. 2022;82:469–82.

    Article  PubMed  Google Scholar 

  4. Adamaki M, Zoumpourlis V. Prostate cancer biomarkers: from diagnosis to prognosis and precision-guided therapeutics. Pharmacol Ther. 2021;228: 107932.

    Article  CAS  PubMed  Google Scholar 

  5. Parker C, Castro E, Fizazi K, Heidenreich A, Ost P, Procopio G, et al. Prostate cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31:1119–34.

    Article  CAS  PubMed  Google Scholar 

  6. Wolf I, Gratzke C, Wolf P. Prostate cancer stem cells: clinical aspects and targeted therapies. Front Oncol. 2022;12: 935715.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Di Zazzo E, Galasso G, Giovannelli P, Di Donato M, Di Santi A, Cernera G, et al. Prostate cancer stem cells: the role of androgen and estrogen receptors. Oncotarget. 2016;7:193–208.

    Article  PubMed  Google Scholar 

  8. Hasan D, Gamen E, Abu Tarboush N, Ismail Y, Pak O, Azab B. PKM2 and HIF-1alpha regulation in prostate cancer cell lines. PLoS ONE. 2018;13: e0203745.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Xia L, Sun J, Xie S, Chi C, Zhu Y, Pan J, et al. PRKAR2B-HIF-1alpha loop promotes aerobic glycolysis and tumour growth in prostate cancer. Cell Prolif. 2020;53: e12918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tran MGB, Bibby BAS, Yang L, Lo F, Warren AY, Shukla D, et al. Independence of HIF1a and androgen signaling pathways in prostate cancer. BMC Cancer. 2020;20:469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Huang M, Du H, Zhang L, Che H, Liang C. The association of HIF-1alpha expression with clinicopathological significance in prostate cancer: a meta-analysis. Cancer Manag Res. 2018;10:2809–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Semenza GL. Dynamic regulation of stem cell specification and maintenance by hypoxia-inducible factors. Mol Aspects Med. 2016;47–48:15–23.

    Article  PubMed  Google Scholar 

  13. Wang L, Zi H, Luo Y, Liu T, Zheng H, Xie C, et al. Inhibition of Notch pathway enhances the anti-tumor effect of docetaxel in prostate cancer stem-like cells. Stem Cell Res Ther. 2020;11:258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cheng JW, Duan LX, Yu Y, Wang P, Feng JL, Feng GZ, et al. Bone marrow mesenchymal stem cells promote prostate cancer cell stemness via cell-cell contact to activate the Jagged1/Notch1 pathway. Cell Biosci. 2021;11:87.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Jamal A, Khan T, Zaidi U, Rizvi QA, Jahanzeb S, Salim A, et al. Highly specific functional equivalence of XN-HPC for optimum CD34+ cell count in harvested allogeneic bone marrow stem cell products. Hematology. 2022;27:232–8.

    Article  CAS  PubMed  Google Scholar 

  16. Marhold M, Tomasich E, El-Gazzar A, Heller G, Spittler A, Horvat R, et al. HIF1alpha regulates mTOR signaling and viability of prostate cancer stem cells. Mol Cancer Res. 2015;13:556–64.

    Article  CAS  PubMed  Google Scholar 

  17. Xiang L, Semenza GL. Hypoxia-inducible factors promote breast cancer stem cell specification and maintenance in response to hypoxia or cytotoxic chemotherapy. Adv Cancer Res. 2019;141:175–212.

    Article  CAS  PubMed  Google Scholar 

  18. Hajizadeh F, Okoye I, Esmaily M, Ghasemi Chaleshtari M, Masjedi A, Azizi G, et al. Hypoxia inducible factors in the tumor microenvironment as therapeutic targets of cancer stem cells. Life Sci. 2019;237: 116952.

    Article  CAS  PubMed  Google Scholar 

  19. Sun X, Lv X, Yan Y, Zhao Y, Ma R, He M, et al. Hypoxia-mediated cancer stem cell resistance and targeted therapy. Biomed Pharmacother. 2020;130: 110623.

    Article  CAS  PubMed  Google Scholar 

  20. Rey S, Schito L, Wouters BG, Eliasof S, Kerbel RS. Targeting hypoxia-inducible factors for antiangiogenic cancer therapy. Trends Cancer. 2017;3:529–41.

    Article  CAS  PubMed  Google Scholar 

  21. O’Reilly D, Johnson P, Buchanan PJ. Hypoxia induced cancer stem cell enrichment promotes resistance to androgen deprivation therapy in prostate cancer. Steroids. 2019;152: 108497.

    Article  CAS  PubMed  Google Scholar 

  22. Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 2020;5:8.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Semenza GL. Hypoxia-inducible factors: coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype. EMBO J. 2017;36:252–9.

    Article  CAS  PubMed  Google Scholar 

  24. Boyd NH, Tran AN, Bernstock JD, Etminan T, Jones AB, Gillespie GY, et al. Glioma stem cells and their roles within the hypoxic tumor microenvironment. Theranostics. 2021;11:665–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hao S, Zhu X, Liu Z, Wu X, Li S, Jiang P, et al. Chronic intermittent hypoxia promoted lung cancer stem cell-like properties via enhancing Bach1 expression. Respir Res. 2021;22:58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rainho MA, Mencalha AL, Thole AA. Hypoxia effects on cancer stem cell phenotype in colorectal cancer: a mini-review. Mol Biol Rep. 2021;48:7527–35.

    Article  CAS  PubMed  Google Scholar 

  27. Keith B, Johnson RS, Simon MC. HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 2011;12:9–22.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zhang M, Zhang Y, Ding Y, Huang J, Yao J, Xie Z, et al. Regulating the Expression of HIF-1alpha or lncRNA: Potential Directions for Cancer Therapy. Cells. 2022;11.

  29. Peng G, Liu Y. Hypoxia-inducible factors in cancer stem cells and inflammation. Trends Pharmacol Sci. 2015;36:374–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kheshtchin N, Arab S, Ajami M, Mirzaei R, Ashourpour M, Mousavi N, et al. Inhibition of HIF-1alpha enhances anti-tumor effects of dendritic cell-based vaccination in a mouse model of breast cancer. Cancer Immunol Immunother. 2016;65:1159–67.

    Article  CAS  PubMed  Google Scholar 

  31. Vieira Pde B, Giordani RB, Macedo AJ, Tasca T. Natural and synthetic compound anti-Trichomonas vaginalis: an update review. Parasitol Res. 2015;114:1249–61.

    Article  PubMed  Google Scholar 

  32. Miyazawa K, Tanaka T, Nakai D, Morita N, Suzuki K. Immunohistochemical expression of four different stem cell markers in prostate cancer: High expression of NANOG in conjunction with hypoxia-inducible factor-1alpha expression is involved in prostate epithelial malignancy. Oncol Lett. 2014;8:985–92.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Venkatesh V, Nataraj R, Thangaraj GS, Karthikeyan M, Gnanasekaran A, Kaginelli SB, et al. Targeting Notch signalling pathway of cancer stem cells. Stem Cell Investig. 2018;5:5.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Teoh SL, Das S. Notch signalling pathways and their importance in the treatment of cancers. Curr Drug Targets. 2018;19:128–43.

    Article  CAS  PubMed  Google Scholar 

  35. Mu R, Zou YK, Tu K, Wang DB, Tang D, Yu Z, et al. Hypoxia promotes pancreatic cancer cell dedifferentiation to stem-like cell phenotypes with high tumorigenic potential by the HIF-1alpha/Notch signaling pathway. Pancreas. 2021;50:756–65.

    Article  CAS  PubMed  Google Scholar 

  36. Byun JY, Huang K, Lee JS, Huang W, Hu L, Zheng X, et al. Targeting HIF-1alpha/NOTCH1 pathway eliminates CD44(+) cancer stem-like cell phenotypes, malignancy, and resistance to therapy in head and neck squamous cell carcinoma. Oncogene. 2022;41:1352–63.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau) (Grant No. 2019ZY023447).

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Authors and Affiliations

  1. Hubei University of Chinese Medicine, Wuhan, 430065, China

    Kun Wu & Minghui Wu

  2. Department of Nephrology, ChongQing JiangJin District Hospital of Chinese Medicine, Chongqing, 402260, China

    Huan Yang

  3. Department of Urology, ChongQing JiangJin District Hospital of Chinese Medicine, Chongqing, 402260, China

    Rui Diao & Hong Zeng

Authors
  1. Kun Wu
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  2. Minghui Wu
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  3. Huan Yang
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  4. Rui Diao
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  5. Hong Zeng
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Contributions

KW and HZ conceived the study design and designed the experiments. KW, MW and HY acquired, analyzed, interpreted the data, and drafted the manuscript. RD and HZ reviewed the manuscript and provided comments. All the authors read and approved the final manuscript and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Hong Zeng.

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Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. All procedures related to the use and care of animals in this study were approved by the ethics committee of Chongqing Jiangjin District Hospital of Chinese Medicine.

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Informed consent was obtained from all individual participants included in the study.

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Wu, K., Wu, M., Yang, H. et al. Hypoxia promotes conversion to a stem cell phenotype in prostate cancer cells by activating HIF-1α/Notch1 signaling pathway. Clin Transl Oncol 25, 2138–2152 (2023). https://doi.org/10.1007/s12094-023-03093-w

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