Mona ElSisi

Egypt

The potential of HOTTIP SNPs as noninvasive diagnostic/prognostic biomarkers for HCC metastasis and siRNAs as promising avenue for targeted-therapy

Mona G. El-Sisi1, Sara M. Radwan1, Sameh S. Ali2, Mohamed Y. Mostafa3, Nadia M. Hamdy1,4
1 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Ain Shams University, 11566, Cairo, Egypt.
2 Research Department, Children’s Cancer Hospital Egypt-57357, Cairo, Egypt.
3 Department of Clinical Oncology, Faculty of Medicine, Ain Shams University, 11566, Cairo, Egypt.
4 The National Committee of Toxicology and Pharmacology Member, ASRT-Egypt

Abstract

Background

Early detection of hepatocellular carcinoma (HCC) remains a significant challenge. In addition, effective stratification is hindered by the lack of dependable biomarkers to predict therapeutic response. Although molecular diagnostics offer clear benefits, their full potential remains untapped, primarily because tissue biopsies are not routinely conducted for HCC. As alternatives, liquid biopsies show promise, but they still face obstacles related to sensitivity& cost. Long noncoding RNAs (lncRNAs), such as the HOXA transcript at the distal tip (HOTTIP), have been linked to HCC.

Methods

This study genotyped the SNPs rs17501292 and rs2067087 as a part of a certain HOTTIP haplotype among 129 nonmetastatic and 69 metastatic HCC patients in the Egyptian population.
Furthermore, this study employed molecular docking to design small interfering RNAs (siRNAs) that target HOTTIP interactions.

Results

Compared with the GG and CC genotypes, the TT and TG genotypes of rs17501292 and the GG and GC genotypes of rs2067087 were associated with a reduced risk of metastasis. Survival analysis highlighted significant relationships between certain SNP genotypes and patient prognosis, with genotypes such as TT (rs17501292) and GC (rs2067087) being associated with improved survival outcomes. Additionally, receiver operating characteristic (ROC) curve analysis underscored the diagnostic and prognostic utility of specific genetic models for rs17501292 and rs2067087, confirming their value as biomarkers for metastasis and survival in patients with HCC.
Molecular docking results lead to the identification of two promising siRNA candidates that could successfully inhibit main downstream target of HOTTIP.

Conclusions

In conclusion, genetic variants in the lncRNA HOTTIP are significantly associated with the risk of metastasis in HCC. Targeting downstream pathways of HOTTIP represents a novel therapeutic approach. This highlights the potential of HOTTIP SNPs as noninvasive diagnostic and prognostic biomarkers for HCC metastasis, and the designed siRNAs present a promising avenue for targeted therapy. Therefore, it’s recommended to perform RNA sequencing analysis to identify more therapeutic targets of HOTTIP.