Abstract
Objective:The aim of this study was investigation the AKT / mTOR signaling pathway components, transcriptional and growth factors, as well as steroid hormone receptors and nuclear factors Brn-3α and TRIM16 expression in the tissue of the primary thyroid tumor and metastases, depending on the BRAF- V600E status. Material and Methods:The study was enrolled 20 patients with PTCs, who underwent surgical treatment. They were divided into negative BRAF-V600E status (12 people), positive BRAF-V600E status (8 patients). Mutation status was assessed in paired metastatic tissue samples. The molecular marker expression was determined by real-time PCR. The Real-time-PCR-BRAF-V600E reagent kit evaluated the BRAF-V600E mutation. Results:A decrease in the PDK kinase, PTEN, VHL mRNA level in primary cancers was noted, compared with metastases’ tissue. An increase in AKT, GSK-3β, mTOR, 70s 6 kinase was revealed in cancers with point mutation compared with the primary tumor without a mutation. Positive mutation status was accompanied by an increase in NF-κB p65, NF-κBp50, VEGF HIF-2 VHL level compared to the primary tumor with negative BRAF-V600E status. In the metastases with the BRAF-V600E point mutation, a decrease in the PDK kinase, HIF-1; VHL; TRIM16, and ERα expression was observed, compared to lymph node metastases (LNMs) without the mutation. The concordance in the BRAF-V600E tumor status and LNMs was observed only in 50% of patients. If the BRAF gene status did not match PTCs and LNMs, an increase in the mTOR, NFkBp65, VHL, and ERα mRNA levels was found in the PTCs. In LNMs, there was an increase in the c-RAF PTEN NFkBp65 VHL expression compared to non-concordant ones. Conclusion:The heterogeneity in the primary tissue’s expression profile and metastases was noted. The BRAF-V600E mutation can affect the molecular characteristics both in the primary cancers and metastases. The discrepancy between the mutant status and the molecular factors expression variability in the primary tumor and LNMs determines its progression.
Highlights
Thyroid cancer is a dynamic disease; during disease, cancers generally become more heterogeneous (Albini et al, 2012)
Positive mutation status was accompanied by an increase in NF-κB p65, NF-κBp50, VEGF HIF-2 von Hippel-Lindau (VHL) level compared to the primary tumor with negative BRAF-V600E status
NF-κBp 65, NF-κBp50, VEGF, HIF2; VHL elevated mRNA level by 10.6; 13.5; 240.6; 11.5; 368.5 times found in tumors with mutation, respectively, compared to the primary tumor with the wild variant of the BRAF gene
Summary
Thyroid cancer is a dynamic disease; during disease, cancers generally become more heterogeneous (Albini et al, 2012). Thyroid cancer is a heterogeneous group of diseases. The current molecular markers that have received the most attention in thyroid cancer include BRAF,.point mutations, and PAX8/PPARG and RET/PTC rearrangements (Bhagirath et al, 2019). Despite the rapidly developing field of molecular markers, several limitations exist. The long-observed age-associated mortality risk in PTC is dependent on BRAF status; age is an intense, continuous, and independent mortality risk factor in patients with BRAF-V600E mutation but not in patients with wild-type BRAF.
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