الفهرس 
Hepatocellular carcinomaOnly 14 pages are availabe for public view
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Abstract
RNA editing is an integral process in generating the diversity of cellular RNA signatures. The best characterized type of RNA editing is A to I (adenosine to inosine) that catalyzed by the ADAR family proteins. HCC is a heterogeneous tumor displaying variable genetic and epigenetic changes. In HCC, aberrant RNA editing may lead to tumor specific transcriptome diversity. Recently, the nutri-epigenomic studies are focusing on the beneficial changes of dietary agent such as pterostilbene on gene expression through epigenetic modifications. However, the effect of pterostilbene on ADAR enzymes expression or RNA editing in HCC has not been investigated.
The aim of our work was to investigate the effect of pterostilbene on hepatic gene expression of Adars in DEN-induced rat model of HCC. We assessed the potential effects of pterostilbene at two levels; “co-exposure chemo-prevention” in which pterostilbene was co administered with DEN from the first week of the study and “post-exposure chemo-prevention” in which pterostilbene treatment started after the onset of the key DEN-induced histopathological changes.
The current study was conducted at Medical Biochemistry Department, Faculty of Medicine, Ain Shams University from October 2018 to March 2019.
Our results revealed that DEN-induced hepatocarcinogenesis indicated by the appearance of prominent hepatic nodules with loss of hepatic architecture and appearance of malignant hepatocytes exhibiting marked pleomorphism, high nucleo-cytoplasmic ratio, prominent nucleoli and frequent mitotic figures. Regarding pterostilbene administration, it attenuates DEN-induced hepatocarcinogenesis; pterostilbene-treated groups exhibited an improvement of the hepatic architecture and minimal atypia of hepatocytes compared to their respective untreated HCC group.
Noteworthy, untreated HCC group exhibited a significant increase in Adar1 alongside a decrease in Adar2 relative expression levels. While pterostilbene treated groups had lower expression of Adar1 and higher expression of Adar2 in comparison to untreated HCC groups. Therefore, we thought that pterostilbene could alleviate the disrupted A-to-I editing enzymes and the prominent effect was in HCC rats received pterostilbene in 6th week of the study “post-exposure effect” in comparison to the group receiving Pterostilbene with DEN from the start of the study.
As expected, liver enzymes and AFP levels were higher in untreated HCC rats, while serum albumin level was lower compared to the control group (p<0.05). In the present study, pterostilbene treatment attenuates DEN-induced hepatocarcinogenesis; pterostilbene-treated groups exhibited a significant reduction in liver enzymes and AFP with improvement of serum albumin reflecting improvement of the synthetic function of the liver.
This study demonstrated that pterostilbene administration had no effect in non-HCC rats either at histological or biochemical levels, or relative expression of ADARs comparing to the control group.
The salient results revealed a positive significant correlation between the relative expression of Adar1 and liver weight, liver enzymes, and AFP while a negative significant correlation with serum albumin was detected (p<0.05). The hepatic expression of Adar2 had a negative significant correlation with transaminases and AFP (p<0.05). On the other hand, no significant correlation was detected between the expression of Adar2 and liver weight and serum albumin.
Conclusion
The nutri-epigenomic agent “pterostilbene” may have a chemo-preventive effect on DEN-induced HCC in rat model. As there was an improvement in hepatic architecture in treated HCC rats compared to non-treated HCC group. At the biochemical level, an improvement in liver enzymes, AFP, and serum albumin levels were noticed. Also, pterostilbene alleviated the disrupted expression status of Adars enzymes. These effects were apparent in HCC group received pterostilbene after 5 weeks of the study “post-exposure group”. But our results are inconclusive and further studies are needed to confirm these findings.
Recommendations
• Further studies should be done to prove our findings with different doses of pterostilbene either in animal models or HCC cell lines.
• Future research should be done to clarify the exact mechanism(s) of pterostilbene on the expression of A-I editing enzymes. Also, these studies should address whether ADAR editing is a driver of cancer progression or simply a passenger alteration.
• Further sequence analysis is mandatory to identify novel key targets of ADAR enzymes that mediate cell proliferation.
• It is recommended to investigate the primary origin of ADAR1 and 2 mis-regulation, and when they appear in the multistep genesis in HCC.