الفهرس 
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Abstract
People from all over the world are affected by HCC. There will be 905,677 new cases and 830,180 fatalities in 2020, according to projections. It will become the world’s 5th much more common cancer and the 3rd major contributor to murder due to cancer.
It ranked first both cancer incidence and mortality in Egypt in 2020, with 20.7 percent of newly diagnosed cases (about 27,895 cases) and 29.8 percent of cancer-related deaths (26,523 deaths). Males had a larger rate of new cases than females, with 27.3 percent compared to 14.3 percent for females.
Although liver transplantation or resection is the most effective treatment for HCC, about 30% of patients are suitable. Nonsurgical candidates are frequently those with locally advanced disease, low liver function, other comorbidities, and/or poor performance status.
For non-surgical HCC patients with tumors less than 3 cm that are largely positioned distant from major blood arteries, bile ducts, and abdominal organs, radiofrequency ablation (RFA) provides an alternative curative therapy option. It works well on tumors that are less than 3 cm in diameter and are primarily positioned distant from important blood vessels, bile ducts, and abdominal organs. Some HCC patients are not candidates for RFA due to the tumor’s location, intrahepatic bile duct dilatation, and disease volume; for these patients, transcatheter arterial chemoembolization, radioembolization with Yttrium-90 microspheres, and external beam radiation therapy are options (RT).
Until recently, apoptosis was thought to be the only molecularly regulated type of cell death, whereas necrosis was supposed to represent uncontrolled cell death. However, the discovery of particular pharmacological inhibitors of necrotic cell death, as well as genetic, biochemical, and functional data, has recast necrosis as a molecularly regulated mode of cell death.
Necroptosis is an adaptive immune response that is triggered to ensure the removal of damaged cells and the organism’s general health. Necroptosis is similar to apoptosis in that it is activated in a controlled manner, but it possesses the physical hallmarks of necrosis. This alternative approach’s broad yet understated repercussions illustrate its biological value. As with apoptosis, necroptosis has been discovered to be a two-edged sword.
TNF super-family receptors, TLR3, TLR4, and TNFR1, can cause necroptosis, which is divided into three groups based on the circumstances that cause it: (1) TNF stimulates extrinsic necroptosis, (2) ROS stimulates intrinsic necroptosis, and (3) Ischemia stimulates intrinsic necroptosis. TNF-mediated necroptosis is a type of necroptosis in which TNF binds to a complementary receptor, forming a short-lived membrane signaling complex that includes TRADD, FADD, RIPK1, TRAF2/TRAF5, and cIAP1/cIAP2.
The pro-survival action of NF-кB is mediated by cIAP1/2 and cFLIPL, and it plays a critical role in counteracting TNF’s cytotoxic effect
Caspase-8 inhibits the activity of RIPK3 and so stimulates exogenous apoptosis and deactivates necroptosis. Caspase-8 inhibition causes RIPK1 activation via deubiquitinating mediated by CYLD. Although both RIPK3 and RIPK1 are required for necroptosis induction, when RIPK3 is over-expressed in cells, it can trigger necroptosis on its own.
When RIPK3 is stimulated, it phosphorylates MLKL, which is involved in necroptosis induction. MLKL has two functions: (1) it acts as a platform in the plasma membrane for the recruitment of Na+ or Ca++ channels, and (2) it stimulates the creation of pore in the plasma membrane by interacting with the amino terminus of phosphatidylinositol.
Methods In order to achieve the aim the present study were carried out in the following sequence:
1- Cell culture of HepG2 cells (obtained from CERRMA Center, Faculty of Medicine, Alexandria University)
2- Treatment of cultured cells with radiation according to planned doses.
3- MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) Assay for cytotoxicity.
4- RNA Extraction
5- Complementary DNA synthesis by reverse transcription.
6- Quantitative determination of (MLKL, RIPK3 & Caspace8) gene expression by real time polymerase chain reaction (RT-PCR).
from the results of our study we can conclude that
1- A dose and time dependent decrease in HepG2 cell viability upon exposure to increasing doses of ionizing radiation.
2- Exposure to ionizing radiation is associated with a significant upregulation of necroptotic modulators RIPK3 and MLKL in a dose and time dependent manner.
3- Apoptotic marker caspase 8 have minimal role in radiation induced cell death, limited to lower doses and shorter time post irradiation.
from 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 and MLKL expression by epigenetic modification can help confirming its role in radiation induced cell death response.
3- Further investigation of the possible MLKL-mediated positive feedback role in activation of necroptotic pathway through RIPK3 upregulation is required.