الفهرس 
Review of LiteratureOnly 14 pages are availabe for public view
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Abstract
Liver cancer remains a major global health concern, and the most frequent type of liver cancer is hepatocellular carcinoma (HCC), accounting for approximately 90% of all cases, with rising incidences every year Llovet et al. (2021). HCC is generally asymptomatic in the early, more treatable stages of the disease; however, it is commonly discovered at an advanced stage with a poor prognosis (Yu et al., 2013). Its aetiology, tumour growth, and progression are all varied in reference to molecular mechanisms. It is a highly diverse disease in terms of aetiology, molecular carcinogenic mechanisms, and biological behaviour, with differences in hepatocyte growth factor expression, intracellular signalling, protease and matrix metalloproteinase expression, and oncogenic transformative expression (Ho et al., 2016; Rizzo et al., 2022). Almost every carcinogenesis pathway is altered to some degree in HCC, making it challenging to pinpoint feasible molecular treatment ‘targets’ (Gong et al., 2020).
AGO and PIWI are two subclasses of argonaute family proteins, according to their evolutionary aspects of PIWI, unlike AGO protein expression, they are usually restricted to germ cells (Homolka et al., 2015). The structure and function of the PIWI family is highly conserved across species. PIWIL1/HIWI, PIWIL2/HILI, PIWIL3, and PIWIL4/HIWI2 are the four human designated proteins (Ishizu et al., 2012).
The aberrant expression of PIWI proteins has been linked to several cancer hallmarks, they include maintaining proliferative signalling pathways, evading growth suppressors, activating invasion and metastasis, mediating genomic instability, accumulation of mutations, and boosting cell growth, to mention a few (Quinn et al., 2015). The molecular mechanisms underlying PIWI’s oncogenic activity and involvement in the regulation of carcinogenesis has yet to be fully understood (Chen et al., 2021; Meseure et al., 2020). Breast cancer, gastric cancer, and liver cancer have all been connected to PIWIL protein and mRNA variants (Cui et al., 2011; Iliev, Fedorko, et al., 2016; Tsujiura et al., 2014). Aberrant HIWI expression has been linked to the beginning and progression of seminoma and colorectal cancer according to (Lee et al., 2012; Li et al., 2021) . However, data on their definitive roles in HCC or prognostic values is limited ( Rojas-Rios & Simonelig, 2018).
Midkine (MDK), was found to be involved in the early phases of retinoic acid-induced differentiation(Yao et al., 2014). Its binding properties were associated with multiple tumorigenesis and carcinogenic interactions. MDK was previously identified as one of five promising novel biomarkers for detecting hepatocellular carcinoma, with the capacity to distinguish between early and later stages of disease progression.
This study aimed to determine the efficacy of the 4 PIWIL mRNA transcripts in humans (PIWIL1/HIWI, PIWIL2, PIWIL3/HILI, and PIWIL4/HIWI2) as diagnostic and prognostic markers for HCC patients. A comparative assessment of MDK and PIWI as diagnostic biomarkers was also conducted with AFP, using ELISA. And PIWIL2 was assessed for protein expression pattern by IHC. Blood samples from 150 HCC patients and 25 seemingly healthy controls were collected. Liver tissue from 50 patients undergoing curative liver resection was also selected with the inclusion of tumorous and non-tumorous sections of the liver. Total RNA was extracted from all samples, then cDNA synthesis was conducted followed by quantitation of relative expression for all PIWIL mRNA transcripts via real-time PCR, IHC was done for PIWIL2, then ELISA was done for MDK, PIWI, and AFP via commercially available kits in the sera of 50 patients and 25 healthy controls.
The results indicated the following:
• The pattern of expression of PIWIL mRNA in HCC was significantly overexpressed in serum and tissue samples (P<0.001).
• PIWIL2 was highly expression in tissue via immunohistochemistry (P<0.05).
• There is a strong correlation between the age of patients, and tumour grades for PIWIL1, 2, and PIWIL4.
• The is a strong association between PIWIL2 and tumour patterns (Acinar Vs Solid tumour types)
• PIWIL mRNAs are a possible diagnostic/ prognostic marker for HCC from ROC curve and logistic regression analysis (P<0.05)
• ELISA results from commercially available kts indicated that Midkine showed the highest significance for protein expression in serum of HCC patients compared to AFP and PIWI proteins, and ROC curve analysis showed similar sensitivity and specificity for AFP and MDK but not for PIWI, indicating the need for exploring more customized kits.