الفهرس 
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Abstract
Hepatocellular carcinoma is a global disease with different epidemiological statistics depending on where you live. It is the world’s fifth most common cancer and the third leading cause of cancer-related mortality, with an estimated 830,180 deaths and 905,677 new cases each year (Sung et al., 2020).
Necroptosis has been proposed to play a role in cancer biology, including oncogenesis, cancer metastasis, cancer immunity, and cancer subtypes, in addition to its critical involvement in viral infection and development (Seehawer et al., 2018; Stoll et al., 2017). The following dual effects of necroptosis on cancer have been demonstrated as a result of the fusion of apoptosis and necrosis: on the one hand, key mediators of the necroptotic pathway have been suggested to promote cancer metastasis and progression (Strilic et al., 2016; McCormick et al., 2016); on the other hand, necroptosis is reportedly a ”fail-safe” mechanism that protects against
The aim of our study was to investigate the pattern of activation of some necroptotic cell death mediators in response to ionizing radiation exposure in hepatocellular carcinoma cell line HepG2.
The results of our investigations demonstrated a dosage dependent and time-dependent decline in HepG2 cells viability in response to exposure to ionising radiation. In irradiated cells, we looked into a variety of pro- and anti-survival molecular targets that could be potential radio-sensitization targets. Quantitative analysis of the inhibitor of apoptosis protein (cIAP1) revealed an early rise in fold change at lower radiation doses in the current investigation (2 and 4 Gy) With increasing radiation doses, there was a decrease in fold change of expression 24 hours after irradiation, although all of these changes were insignificantly different from the unirradiated control group. cIAP1 expression was much lower 48 hours after 2 Gy irradiation than it was 24 hours later, but it did not differ from the control group at any of the radiation doses.
A significant downregulation of TRAF2 was observed 24 h post irradiation with doses up to 10 Gy. However, although TRAF showed a significant upregulation 48 h post irradiation with 2 Gy, this increase in expression was normalized with higher radiation doses but was significantly higher than 24 h groups at 2, 6 and 10 Gy. TRADD gene expression was shown to be significantly upregulated after exposure to radiation at doses ranging from 4 to 8 Gy. When the follow-up time was extended to 48 hours, the expression continued to rise dramatically. At both time intervals, the maximal values of TRADD expression were seen at 4 and 6 Gy. With doses ranging from 4 to 8 Gy, RIPK1 expression revealed a substantial upregulation 24 hours after irradiation, peaking at 4 Gy before dropping significantly at 10 Gy. However, at 48 hours after irradiation, a similar trend was found, no significant difference was observed between the two time intervals.
from the results of the current study we can conclude that:
1- Exposure to ionizing radiation is associated with a significant down-regulation in anti-apoptotic modulators (cIAP1/2, TRAF2) in a dose and time dependent manner.
2- TRADD and RIPK1 are key modulators of radiation-induced cell death pathways.
3- TRADD, apoptosis modulator, may contribute to cell death through delayed apoptosis at 48 h post irradiation.
4- Necroptosis modulator RIPK1 emerged as a promising modulator of cell death at low and high doses and at earlier time compared to TRADD
Form the results of the current study we can suggest that:
1- Further analysis of necroptosis key modulators is required to provide better understanding of the death modes in radiation resistant cancer cells.
2- Modulation RIPK1 expression by epigenetic modification can help confirming its role in radiation induced cell death response.