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In hepatocellular carinoma (HCC) tumors, a correlation has been observed between a high TERT expression and specific regions of the TERT promoter region, particularly around the start codon site. Elevated TERT expression is notably associated with rs2853669 and the -124C>T mutation located within the promoter region spanning -270 to -31bp (Fig. 7C,D). These findings suggest the possibility of long-term, sustained DNA methylation in the TERT promoter that interferes wtih rs transcription factor binding. . .
DNMT1-mediated methylation of promoter DNA can hinder the binding of transcription factors to their respective promoter sequences e.g., AGCG. Supporting evidence shows that CpG methylation suppresses E2F1 binding to promoter regions ,derived from dihydrofolate reductase;c-myc or c-myb as demonstrated through luciferase assay in human osteosarcoma (Saos2) cell lines, (Ref: CpG methylation as a mechanism for the regulation of E2F activity). T Collectively, these data indicate that TERT transcription is difficult to activate due to a repressive environment thatmaintains the gene in an inactive state. Furthermore, certain single nucleotide polymorphisms (SNPs) involved in telomere maintenance have been linked to the survival of HCC patients infected with hepatitis B virus(HBV)(Ref). One key variant, rs13167280 (IVS3-24 C > T),located in intron 3 of the TERT gene. Has been associated with a reduced risk of HCC progression, as reported by Jung et al. (Ref) However, no significant association was found between rs2853669 and HCC risk in the same study.
Our current data demonstrated that rs2853669 variant, when combined with -124C>T mutation of the TERT promoter, enhances TERT expression. This combination not only increcases TERT activity but also contributes to telomere length,HCC recurrence, and overall mortality.
In conclusion, this study suggests that SNPs, when coupled with other genetic alterations, play a critical role in predicting recurrence and prognosis in patients with hepatocellular carcinoma.
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