HOTTIP-Variants in Liver Cancer Metastasis Prognosis: A Clinical Study with Bioinformatics and siRNAs Targeting HOTTIP-WDR5 via Molecular Docking, a Step-Toward ncRNA Precision

Early detection of hepatocellular carcinoma (HCC) remains challenging due to limitations including the lack of reliable biomarkers. While molecular diagnostics hold promise, their use is limited because tissue biopsies are not routinely performed in HCC. Long non-coding RNAs (lncRNA), such as HOXA transcript at the distal tip (HOTTIP), have been implicated in HCC, with single-nucleotide polymorphisms forming haplotypes that may influence disease progression. This study investigated the clinical relevance of HOTTIP SNPs rs17501292 and rs2067087 in 198 Egyptian HCC patients (129 non-metastatic, 69 metastatic). Moreover, molecular docking was used to design small interfering RNAs (siRNAs) targeting HOTTIP. Genotypes <i>TT</i> and <i>TG</i> (rs17501292) and <i>GG</i> and <i>GC</i> (rs2067087) were associated with reduced metastatic risk compared to <i>GG</i> and <i>CC</i> genotypes, respectively. Survival analysis revealed that <i>TT</i> (rs17501292) and <i>GC</i> (rs2067087) genotypes correlated with improved outcomes. ROC curve analysis confirmed the diagnostic and prognostic value of specific genetic models, affirming their value as biomarkers for metastasis and survival. Molecular docking identified two promising therapeutic candidates. Overall, we can conclude that HOTTIP SNPs may serve as promising potential non-invasive biomarkers for HCC metastasis and prognosis, while the identified siRNAs offer a novel targeted therapeutic approach.