Hepatocellular carcinoma (HCC) is among the most common malignancies currently encountered in Egypt owing to the high prevalence of viral hepatitis over the last 30 years [1], [2]. Previous studies have focused on the development of ideal effective noninvasive biomarkers that can help in the early diagnosis, treatment, and prognosis of HCC among hepatitis C virus (HCV) patients with liver cirrhosis (LC) [3], [4], [5]. This challenging disease with diverse genetic basis has attracted several researchers toward the diagnostic potential of circulating microRNAs in HCC.

Malignancy-specific changes in microRNA expression are common in various cancers, and thus, microRNAs could play a fundamental role in cancer occurence, progression, and potential therapeutic targets [6], [7]. The direct measurement of tissue microRNAs is invasive and inconvenient, whereas the serum measurement of microRNAs is much less invasive and is correlated with the levels of many microRNAs in the liver [8], [9]. Tissue microRNAs may reach the serum either actively through secreted exosomes and viral particles or passively after apoptosis and necrosis [10]. Thus, the serum microRNA levels may reflect the microRNA activity in the liver.

With the introduction of the highly successful direct-acting antivirals (DAAs), surprisingly a high incidence of HCC was noted among HCV patients post DAA therapy despite the high rates of HCV clearance. The most relevant hypothesis that could explain HCC post DAA therapy is that the dramatic HCV clearance may provoke immune cell alteration, cytokine network imbalance, and angiogenesis [11]. Although previous studies have confirmed the changes in the circulating microRNA profile pre and post DAA therapy in cases with and without HCC, further research is still needed [12].

MicroRNA 21-5p is associated with human liver pathogenesis and disease evolution, from hepatitis, hepatic fibrosis, and cirrhosis to HCC [13]. Transforming growth factor b (TGF-b), a mediator of liver fibrosis, fosters the expression of microRNA 21-5p, which consecutively decreases the expression of Sma- and Mad-related protein 7 (SMAD7), a negative regulator of TGF-b signaling [14]. Moreover, MicroRNA 122-5p has been involved in the regulation of different metabolic pathways in hepatocytes with significant downregulation in the liver tumors [15]. Moreover, MicroRNA 222-3p is a promising biomarker for the progression of HCV-related hepatic fibrosis with higher levels in HCC cirrhotic patients compared with patients without cirrhosis [16], [17].

As far as we know, no study has elaborated the significance of microRNA 222-3p, microRNA 21-5p, and microRNA 122-5p in HCV-related HCC and HCC post DAA therapy among Egyptian patients. Thus, this research aims to investigate their diagnostic potential in HCV-related HCC pre-/post-HCV DAA therapy.