الفهرس 
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Abstract
S UMMARY
epatocellular carcinoma (HCC) is a worldwide common death problem. It is considered as the second most common cause of cancer-associated fatalities. Incidence of HCC is rapidly growing in the West because of the epidemic increases of its risk factors like alcohol, fatty liver and viral hepatitis. MicroRNAs (MiRs) are small non-coding RNA segments of nearly 22 nucleotides, controlling gene expression. A single miR regulates multiple genes, therefore a small change in miR expression may effect the expression of hundreds of target genes.
In order to improve the diagnosis of early stage of HCC and to discriminate between Hepatitis C Virus (HCV) and HCC stages, the present study aimed at evaluating the expression level of miR-122, miR-221 and cyclin G1 as well as their combination in HCV and HCC patients in order to evaluate whether they could be used as sensitive biomarkers for HCC development and its different stages as surrogate biomarkers for α- fetoprotein (AFP).
The study included 28 HCV infected patients and 36 HCC patients, further subdivided into stage I HCC patients (n=10), stage II HCC patients (n=14) and stage III HCC patients (n=12). In addition, normal healthy individuals (n=13) were recruited into the study. MiR-122, miR-221 and cyclin G1 gene expression levels
H
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were determined by quantitative real time polymerase chain reaction analysis. Serum AFP level was determined using ELISA.
The obtained results are summarized as follows:
A statistically significant increase in serum AFP expression level in HCV and HCC patients was recorded compared to the control group. There was a non-significant change in the serum level of AFP in stage I HCC patients, compared to HCV patients as well as healthy subjects. However, a sharp significant increase in AFP serum level was recorded in stages II and III HCC patients, compared to stage I HCC and HCV patients, as well as healthy subjects. Accordingly, AFP is considered a poor diagnostic biomarker in differentiating stage I HCC patients from HCV patients.
Patients with HCV, HCC and different stages of HCC demonstrated a significant increase in serum miR-221 and cyclin G1 expression levels, compared to healthy subjects. Moreover, serum cyclin G1 was able to discriminate between HCV and HCC patients, while serum miR-221 was unable to differentiate between both groups.
Serum miR-221 and cyclin G1 were able to differentiate between HCV and stage I HCC patients, whereas only cyclin G1 was able to differentiate between HCV and stage II & III HCC patients, demonstrating the importance of miR-221 in the induction of proliferation of early-stage HCC cells.
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A non- statistical difference was obtained in miR-122 expression level between HCV patients and control group. On the other hand, HCC patients manifested a significant elevation in serum miR-122 expression, compared to HCV patients and healthy subjects.
Stage I, II & III HCC patients manifested a significant increase in serum miR-122 expression level, compared to healthy subjects. On the other hand, miR-122 was able to discriminate between HCV and HCC patients with high sensitivity and specificity as well as different stages of HCC.
The combination of AFP+miR-122, AFP+cyclin G1, miR-122+cyclin G1 and AFP+cyclin G1+miR-122 gave rise to AUC values higher than those of each marker individually to discriminate between HCV and HCC patients with high sensitivity and specificity.
The combination of miR-122+221, miR-122+cyclin G1, miR-221+cyclin G1 and miR-221+ cyclin G1+miR-122 gave rise to the Area Under Curve (AUC) values higher than those of each marker alone to discriminate between HCV and stage I HCC patients.
The combination of miR-122+cyclin G1 gave rise to AUC values higher than those of each marker individually to discriminate between HCV and stage II & III HCC patients with high sensitivity and specificity.
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In conclusion, the current study suggests that serum miR-122 and cyclin G1 may be used as non-invasive diagnostic biomarkers for HCC. In addition, serum miR-122, miR-221 and cyclin G1 either alone or combined can be useful biomarkers, rather than AFP, in discriminating between HCV and early stage I HCC patients.