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Article

Hepatocyte nuclear factor 4, alpha (HNF4A): A potential biomarker for chronic hypoxia in MCF7 breast cancer cell lines

Malek Zihlif1★, Zainab Zakaraya2, Feda' Hamdan3, Ahmad Sharab4, Farah Tahboub4, Shahd Qudsi4, Sara Feras Abuarab5, Rajaa Daghash5, Ahmad R. Alsayed5★ Corresponding author

  1. 1Department of Pharmacology, School of Medicine, The University of Jordan, Amman, Jordan.
  2. 2Biopharmaceutics and Clinical Pharmacy Department, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan.
  3. 3Gene Regulatory Mechanisms and Molecular Epigenetics Laboratory, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
  4. 4Department of Pharmacology, The University of Jordan, Amman, Jordan.
  5. 5Department of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy, Applied Science Private University, Amman 11937, Jordan.

CORRESPONDENCE

Malek Zihlif

Department of Pharmacology, School of Medicine, The University of Jordan, Amman, Jordan.

m.zihlif@ju.edu.jo

Received: 17-06-2024; Accepted: 30-10-2024.

Volume 23, Issue 3 · pp. 3227 · PUBLISHED 3 September 2025 · DOI: 10.18549/PharmPract.2025.3.3227

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ABSTRACT

Introduction: Hypoxia mediates cancer hallmarks and results from low oxygen levels due to irregularities in tumor vascularization or when the bulk of the tumor prevents oxygen diffusion and stimulates angiogenesis to compensate for low oxygen. Aims: This study aims to identify significant biomarkers associated with tumor hypoxia, focusing on prolonged exposure to hypoxic conditions. Methods: The breast cancer cells (MCF7) were exposed to 8-hour hypoxic episodes (1% oxygen) three times per week for 60 episodes and once weekly for 72 hours for a maximum of 12 episodes. After 60 and 12 episodes of hypoxia, changes in gene expression were profiled using a hypoxia RT-PCR array and compared to normoxic cells. An assay was performed after 60 and 12 episodes of hypoxia to determine the effect of hypoxia on angiogenesis migration. Results: The expression of the Hepatocyte Nuclear Factor 4 gene increased by 32.71-fold following exposure to 12 hypoxic injections and by an additional 14.95-fold following exposure to 60 hypoxic injections. After twelve episodes of hypoxia, the capacity for cell migration increased. Conclusion: This study provides empirical support for the notion that cellular exposure to prolonged durations of hypoxia, specifically three months, induces expression changes distinct from those induced by fleeting durations of hypoxia, which are less than weeks and hours. The study hypothesized that HNF4A could serve as a viable biomarker for tumor hypoxia and a major contributor to the response of MCF7 breast cancer cells to protracted hypoxic conditions.

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    Zihlif, M., Zakaraya, Z., Hamdan, F., Sharab, A., Tahboub, F., Qudsi, S., Abuarab, S. F., Daghash, R., & Alsayed, A. R. (2025). Hepatocyte nuclear factor 4, alpha (HNF4A): A potential biomarker for chronic hypoxia in MCF7 breast cancer cell lines. Pharmacy Practice, 23(3), 3227. https://doi.org/10.18549/PharmPract.2025.3.3227