Problems of Radiation Medicine and Radiobiology

N. A. Golyarnik¹, I. N. Ilienko¹, L. M. Zvarych¹, M. O. Vorobyov², D. A. Bazyka¹

¹ State Institution «National Research Center for Radiation Medicine of the National Academy of Medical
Sciences of Ukraine», 53 Yuriia Illienka Str., Kyiv, 04050, Ukraine
² Municipal non-profit enterprise «Zaporizhzhia Regional Antitumor Center» Zaporizhzhia Regional
Council, 177-a Kulturna Str., Zaporizhzhia, 69040, Ukraine

CHARACTERISTICS OF CYCLIN D1-MEDIATED REGULATION OF CELL CYCLE OF PERIPHERAL BLOOD LIMPHOCYTES OF CHORNOBYL CLEAN-UP WORKERS AND PERSONS WITH MALIGNANT NEOPLASMS OF THE ORAL CAVITY, OROPHARYNX AND LARYNGOPHARYNX

Objective: to explore proliferative potential of peripheral blood lymphocytes of Chornobyl clean-up workers and persons with malignant neoplasms of the oral cavity, oropharynx and laryngopharynx by level of expression of cyclin D1 and quantitative parameters of cell cycle.
Materials and methods. A total of 294 men aged (58.47 ± 7.32) were surveyed, 215 of them were Chornobyl clean-up workers (1986–1987), exposed at the dose range 10.43–3623.31 mSv; 49 persons of the control group and 30 persons with malignant neoplasms of the oral cavity, oropharynx and laryngopharynx at III, IVА and IVВ stages of the disease. The analysis of parameters of cell cycle and proliferative activity of peripheral blood (PB) lymphocytes was performed using the flow cytometry. The evaluation of distribution of cells by G₀/G₁, S, G₂/M cell cycle phases was done in vivo and in in vitro. Proliferative potential was analyzed by level of expression of cytoplasmic protein of cyclin D1.
Results. Proliferative potential of PB lymphocytes of Chornobyl clean-up workers and persons with malignant neoplasms of the oral cavity, oropharynx and laryngopharynx was assessed. An increase in the level of spontaneous сyclin D1 expression and disturbance of сyclin D1-dependent regulation of cell cycle of PB lymphocytes after mitogen activation were determined in the Chornobyl clean-up workers. An increase in pool of cells in the S- and G₂/M-phases of cell cycle was detected, which characterizes high proliferative potential of PB lymphocytes. These changes are most pronounced in the subgroup of persons with a radiation dose of D < 500 mSv, and in persons with oncological pathology.
Conclusions. A positive linear dependence has been established between the radiation dose and the number of cells in the S-phase of cell cycle in the subgroup of Chornobyl clean-up workers with a radiation dose of D < 500 mSv. The detected changes of cyclin D1-dependent regulation of cell cycle and proliferative status of lymphocytes depend on the radiation dose, can be a manifestation of genome instability and be a cause for risks of oncogenesis, in a remote period after radiation exposure.
Key words: cell cycle, cyclin D1, oncological pathology, radiation, Chornobyl.

Problems of Radiation Medicine and Radiobiology.
2021;26:357-370. doi: 10.33145/2304-8336-2021-26-357-370

full text

1. Alt JR, Cleveland JL, Hannink M, Diehl JA. Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev. 2000;14(24):3102-3114. doi: 10.1101/gad.854900.
2. Qie S, Diehl JA. Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med. 2016;94(12):1313-1326. doi: 10.1007/s00109-016-1475-3.
3. Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer. 2011;8(11):558-572. doi: 10.1038/nrc3090.
4. Thomas GR, Nadiminti H, Regalado J. Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma. Int J Exp Pathol. 2005;6(86):47-363. doi: 10.1111/j.0959-9673.2005.00447.x.
5. Diehl JA, Ponugoti B. Ubiquitin-dependent proteolysis in G1/S phase control and its relationship with tumor susceptibility. Genes. Cancer. 2010;1(7):717-724. doi: 10.1177/1947601910382902.
6. Vermeulen K, Van Bockstaele DR, Berneman ZN. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif. 2003;36(3):131-149. doi: 10.1046/j.1365-2184.2003.00266.x.
7. Sutherland RL, Musgrove EA. Cyclin D1 and mammary carcinoma: new insights from transgenic mouse models. Br Cancer Res. 2002;4(1):14-17. doi: 10.1186/bcr411
8. Keum JS, Kong G, Yang SC, Shin DH, Park SS, Lee JH, et al. Cyclin D1 overexpression is an indicator of poor prognosis in resectable non-small cell lung cancer. Br J Cancer. 1999;81(1):127-132. doi: 10.1038/sj.bjc.6690661.
9. Alao JP. The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention. Mol Cancer. 2007;6(1):24. doi: 10.1186/1476-4598-6-24.
10. Lanni JS, Jacks T. Characterization of the p53-dependent postmitotic checkpoint following spindle disruption. Mol Cell Biol. 1998;18(2):1055-1064. doi: 10.1128/MCB.18.2.1055.