APOBEC۳B as a Key Biomarker in Cervical Cancer: Insights into HPV, HIV, and Genetic Instability

Cervical cancer (CC) is the fourth most common cancer in the world among women, with two histological subtypes named squamous cell carcinoma (۷۰%) and adenocarcinoma (۲۵%). Up to ۹۰% of squamous cell carcinoma cases are associated with persistent HPV infection. Additionally, women with HIV are six times more likely to develop this cancer. Our study aims to identify new biomarkers for cervical cancer associated with HPV and HIV infections, focusing on the P۵۳ pathway through bioinformatics analysis. The impact of relevant SNPs, lncRNAs, and miRNAs was studied to understand their roles in CC progression. Methods: The GSE۶۴۲۱۷ dataset was analyzed using GEO۲R, and the results showed a gene's substantial overexpression. We validated this discovery using ENCORI and GEPIA۲. EnrichR was used to explore relevant pathways, followed by a more detailed examination using KEGG and Reactome databases. SNPs were analyzed using the SIFT, miRNA SNP, and dbSNP databases. One SNP in the coding sequence was selected, and its effects on the target gene were analyzed using the HOPE database. Also, the miRWalk database was used to identify a miRNA and clarify its role in our cancer. Result: GEO۲R analysis identified APOBEC۳B as a gene with significantly high expression in cervical cancer (log FC: ۹.۶۵, adj. p. value < ۰.۰۱). EnrichR and STRING databases showed that APOBEC۳B encodes a cytidine deaminase enzyme that interacts with other APOBEC family members (such as APOBEC۳A, APOBEC۳H, APOBEC۴, and APOB). Pathway analysis (KEGG, Reactome) showed that APOBEC۳B plays a role in turning HIV into double-stranded DNA (dsDNA) by changing cytosine to uracil in single-stranded DNA (ssDNA). This process leads to genetic instability, preventing the proper conversion of viral DNA. In cancer, overexpression of APOBEC۳B can cause mutations in the host’s DNA. These mutations overload the DNA repair systems and can disable crucial tumor suppressor genes like TP۵۳ and RB۱, leading to cancer cell growth. A deleterious SNP, rs۳۶۷۸۵۳۵۷۴ (arginine to cysteine at position ۳۱۱), found using SIFT and analyzed with the Hope database, changes the enzyme's structure and charge, which might interfere with how it interacts with other molecules. This structural alteration can cause uncontrolled mutations by APOBEC۳B, leading to frequent errors in the DNA of host cells. HPV infection can induce APOBEC۳B overexpression. High-risk HPV oncoproteins (such as E۶ and E۷) from types like HPV-۱۶ and HPV-۱۸ increase the risk of cervical cancer by working together to raise APOBEC۳B expression. E۶ and E۷ are well-known for disrupting the p۵۳ pathway, thereby increasing APOBEC۳B mutagenic activity and leading to further genetic instability. miRNA hsa-mir-۶۶۱ (from MirWalk)(bindingp:۱, energy: -۲۷.۴, seed:۱, position: ۳'UTR) and lncRNA KCNQ۱۰T۱ (from lncRResearch) were also identified as regulators of APOBEC۳B, potentially influencing cervical cancer progression. However, more research is needed to clarify how they regulate APOBEC۳B expression in cervical cancer. Conclusion: APOBEC۳B is a critical biomarker in cervical cancer, influenced by HPV and HIV infections, leading to significant genetic instability. Practical research is vital to uncover these mechanisms and develop therapies or diagnostics that help manage the disease and improve outcomes.

کلیدواژه ها:

Cervical cancer ، HPV ، HIV ، Microarray analysis ، Biomarker