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Abstract Hepatocellular carcinoma (HCC) is the second leading cause of global cancer-related deaths, especially in patients with liver cirrhosis, and it is the sixth most common malignancy worldwide. The high mortality of HCC patients is linked to delayed diagnosis, leading to limited therapeutic options. Risk factors for HCC include viral infections with hepatitis B (HBV) or C virus (HCV), alcoholism, immune-related liver diseases, nonalcoholic fatty liver disease, obesity, and aflatoxin exposure, and these factors vary with gender, geographic region, and ethnicity. HBV and HCV infections are the most strongly associated risk factors. Long non-coding RNAs (lncRNAs) have been demonstrated as important regulators in diverse human cancers. This study is expected to clear up the potential diagnostic and prognostic role of long non-coding RNA (HOTTIP, ZEB-AS1, and MEG3) in HCC. Subjects were classified into three groups: 1- group I: Patients with HCC on top of chronic HCV and HBV infection. 2- group ||: Patients with liver cirrhosis. 3- group |||: Healthy subject as control. Patients groups were subjected to the following: 1- Full history taking. 2- Thorough clinical examination. 3- 3- Laboratory investigations including measurement of: I. Complete blood count (CBC): Hb level, red blood cells (RBCs), white blood cells (WBCs), and platelets count. II. Liver function tests: serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), total and direct bilirubin, serum albumin (Alb), prothrombin time (PT). 4- Quantification of LncRNA (HOTTIP, ZEB-AS1, and MEG3) relative expression levels by real-time PCR Regarding HOTTIP this study showed that its levels were significantly higher among HCC patients compared to a cirrhotic group and were least among normal controls indicating that it may be considered as a predictive marker for malignant transformation among high-risk cirrhotic patients. In the present study higher HOTTIP levels in HCC patients were significantly linked with nodal and distant metastases also associated with poor overall survival indicating its possible negative association with the patient’s prognosis. In the current study, MEG3 was significantly down-regulated in patients with HCC compared to cirrhotic and normal counterparts. In our study, considerably lower values of MEG-3 were demonstrated with larger tumor size and we noticed that patients with lower MEG-3 values had lower overall survival. In the current study, we found that ZEB-AS1 was significantly higher in HCC compared to cirrhotic patients and their normal counterparts |