Background: By 2025, liver cancer will impact more than 1 million people yearly, and 90% of instances of them will be Hepato Cellular Carcinoma (HCC). The variances in the molecular pathogenesis of HCC depend on the different genotoxic insults and etiologies, which becomes a significant barrier for current therapies. The emergence of cutting-edge strategies based on disproportionality analysis is beneficial for deciphering drugs that may improve the treatment of hepatocellular carcinoma. Moreover, advanced molecular targeted therapies demand a thorough insight into molecular mechanisms involved in the stepwise progression of HCC.
Objectives: This study aims to identify the genetic underpinning of HCC and repurpose the available FDA approved based on the real-world data.
Methods: Gene expression profile datasets encompassing microarray data of Normal, Cirrhosis, Dysplatic nodule, and HCC were analyzed using GEO2R to decipher the cross-talk genes in the stepwise progression of hepatocellular carcinoma. Subsequently, a protein-protein interaction network was constructed between the cross-talk genes using the Search Tool for the Retrieval of Interacting Genes and visualized through Cytoscape. The gene that showed high interaction with other cross-talk genes was shortlisted as a crucial target for HCC. Meanwhile, primary analyses of the FAERS database using Open Vigil 2.1-MeDRA24 identified a handful of drug candidates that may improve the treatment of HCC. Herein, the filtration was done for significant inverse associations (reporting odds ratio -1.96SE < 1 and adjusted P < .05), and implausibility or clinical infeasibility was also checked. These identified drugs were screened against the abovementioned target of HCC by molecular docking studies through extra precision mode (XP) by using Schrodinger tool.
Results: Cdk2 is substantially overexpressed in dysplastic nodules and HCC with a node degree of 46 showed higher interactions with the other cross-talk genes was shortlisted as the potential target. A list of 115 clinically possible drugs exhibiting anticancer activity was identified by disproportionality analysis were screened against cdk2. Angiotensin II receptor blockers, such as valsartan, Irbesartan, and Iosartan showed better docking scores (-7.003, -6.644 and -7.601), amino acid interaction (ASP145, GLU81 and LEU83) and binding energy(-65.93, -51.9 and -65.3) were identified as repurposable drugs.
Conclusions: This study reveals a series of key cross-talk genetic underpinnings from pre-neoplastic lesions to HCC and suggests the pertinence of Angiotensin II receptor blockers as a potential repurposable drugs in the treatment for HCC.
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