الفهرس 
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Abstract
Hepatocellular carcinoma (HCC) is a significant global health issue. It is distinguished by a significant frequency of reoccurrence and unfavorable prognosis. Despite the availability of multiple treatment modalities, hepatocellular carcinoma (HCC) is characterized by a significant death rate and continues to be a challenging and difficult-to-treat disease. Therefore, it is crucial to conduct deeper investigations into the molecular mechanisms implicated in HCC in order to find factors that might be utilized for the advancement of efficacious treatments that enhance patient survival.
This study was a retrospective, case-control investigation undertaken in the Internal Medicine and Pathology Departments of the Faculty of Medicine at Minia University, in partnership with the Minia Oncology Center. The study was conducted between November 2018 and April 2021.
The objective of our study was to examine the hepatic expression of Snail-1, TGFβR2, and CD44 proteins in Egyptian patients with HCV-associated HCC. We aimed to establish a correlation between these protein expressions and the clinicopathological features of the tumor as well as the fate of the disease.
The present study included a total of 60 patients, divided into three groups as follows:
• group I consisted of 20 consecutive patients who had HCV-associated hepatic cirrhosis complicated with HCC. The individuals in question were hospitalized to the Minia Oncology Center specifically for the purpose of undergoing either a liver biopsy or a hepatic lobectomy.
• group II consisted of 20 patients who had liver cirrhosis associated with HCV, but did not have HCC. The individuals were enrolled in consecutive order based on referrals from outpatient clinics at the Internal Medicine Department.
The data of patients diagnosed with hepatocellular carcinoma (HCC) and cirrhosis were obtained from their medical records stored in the archives of the Minia Oncology Center. Eligibility was limited to individuals who possessed sufficient liver tissue and possessed comprehensive clinicopathological data.
• group III consisted of 20 healthy controls who were prospectively selected from participants hospitalized to the General Surgical Department of Minia University Hospital for abdominal surgical operations. The individuals had no medical conditions, had normal liver tissue examination results, and tested negative for anti-HCV and hepatitis B surface antigen (HBsAg) in their blood.
All study participants provided informed consent, following the rules of the Institutional Review Board of the Faculty of Medicine Ethical Committee of Minia University.
The exclusion criteria included patients with:
Cirrhotic patients with severe coagulopathy that contradicts liver biopsy.
Diabetes mellitus (DM), that was diagnosed according to the criteria of American Diabetic Association (2021).
Patients with cirrhosis due to causes other than chronic HCV infection.
Patients with end-organ failure.
Patients underwent organ transplantation.
Patients underwent locoregional treatment for HCC,6 months prior enrollment in this study.
Patients with extra hepatic or hematological malignancies.
Patients with autoimmune diseases.
Patients on steroids and immunosuppressive medications.
All study individuals were subjected to the following:
I-Thorough clinical history
II- Careful clinical examination with special emphasis on:
Vital signs, stigmata of chronic liver disease, and other body systems were examined as well.
III-laboratory investigations; including:
1- Complete blood count (CBC). 2- Complete liver function tests.
3-Prothrombin concentration (PC) and international normalized ratio (INR).
4 -Fasting and 2-hour post-prandial blood glucose levels (FBG, 2h- PPBG).
5-Viral markers: including: anti-HCV, HbsAg and anti-HIV.
6-Alpha-fetoprotein (AFP) in HCC group.
7- Determination of hepatic expression of Snail-1, TGFβR2 and CD44 proteins was done by immunohistochemistry.
IV- Imaging studies:
1-Abdominal ultrasonography
2-Abdominal contrast-enhanced Computerized Tomography scanning.
V-Assessment of functional status of the liver using: MELD (Kamath et al., 2007) and Child-Pugh (Child & Turcotte, 1964) scoring systems in cirrhotic patients.
VI-Staging of HCC that was based on: Tumor Node and Metastasis (TNM) (Kee et al., 2013) and Okuda (Okuda et al., 1985) staging systems.
The current investigation exhibited a significant augmentation in hepatic Snail-1 expression in cirrhotic individuals with hepatocellular carcinoma (HCC) in comparison to those without HCC and the control cohort. Snail-1 had a direct relationship with both the age of the patients and the levels of AFP in the group of cirrhotic patients with HCC. Moreover, our inquiry uncovered a significant association between increased hepatic expression of Snail-1 in individuals with hepatocellular carcinoma (HCC) and a higher occurrence of specific clinical traits. The characteristics encompass an AFP level beyond 100 ng/ml, a tumor size over 5cm, the existence of vascular invasion, and an advanced TNM stage.
The hepatic expression of TGFβR2 was significantly decreased in cirrhotic patients with hepatocellular carcinoma (HCC) compared to both the cirrhotic group without HCC and healthy controls. The study found that there were negative relationships between the expression of TGFβR2 in the liver and both the age of the patients and the levels of AFP.Furthermore, our investigation uncovered a significant association between reduced hepatic expression of TGFβR2 in patients with hepatocellular carcinoma (HCC) and a higher occurrence of AFP levels beyond 100 ng/ml, vascular invasion, and advanced TNM stage.
The hepatic expression of CD44 was significantly higher in cirrhotic patients with hepatocellular carcinoma (HCC) compared to those without HCC and the control group. An association was found between the hepatic expression of CD44 and both smoking exposure and AFP levels, indicating a positive link. Moreover, our investigation unveiled a robust association between increased hepatic expression of CD44 and a greater occurrence of vascular invasion in patients.
Moreover, the three indicators in the current study displayed a noteworthy association with each other. Significant inverse correlations were found between the TGFβR2 protein and both the Snail-1 and CD44 proteins.
The hepatic expression of the three molecules examined in patients with hepatocellular carcinoma (HCC), patients with cirrhosis, and healthy controls remained unaffected by the hepatic functional reserve. This emphasizes their individual significance in this domain.
Conclusions:
• In patients with hepatocellular carcinoma (HCC), the levels of Snail-1 and CD44 were found to be elevated in the liver, whereas the expression of TGFβR2 was reduced.
• The hepatic expression of these molecules was strongly correlated with the unfavorable clinicopathological characteristics of the tumor and was not influenced by the hepatic functional reserve.
• These proteins were detected in various cells that make up the tumor microenvironment.The hepatic expression of these proteins exhibited a substantial correlation, indicating their collective involvement in hepatocarcinogenesis.
• The hepatic expression of Snail-1 protein was increased with weight reduction and aging. In contrast, the reduced expression of TGFβR2 protein was only observed in association with aging.
Recommendation
• Further multicenter studies including a larger sample size, are advised to validate our results.
• Targeting these 3 markers by more studies might be a new direction for more effective therapeutic modalities in HCC patients.