Investigation of the immunological evasion mechanism of papillary thyroid cancers and identification of the pivotal gene implicated in disease recurrence

Papillary thyroid carcinoma accounts for ۹۰% of thyroid cancers. Many PTC cases have a good prognosis, but may develop recurrence, metastasis, or dedifferentiation. PTC is connected to rapid disease progression and poor survival, although its mechanism is uncertain. Underlined mechanisms are examined in this paper. Methods: The study employed a systematic search strategy in the NCBI-GEO and Elsevier databases, using the terms "papillary thyroid cancer", "metastasis", and "recurrence". Analyzing relevant publications, classifying the findings, and concluding the acquired information and study. Results: Among genes significantly upregulated in PTC tumor tissue compared to adjacent normal tissue, the ZCCHC۱۲ gene exhibited the most pronounced increase in expression, indicating its role as a potent oncogene. Cytokine receptors, the TP۵۳ signaling pathway, blood coagulation, epithelial-to-mesenchymal transition (EMT), and tissue graft rejection mechanisms are modified in papillary thyroid carcinoma (PTC). Altered immune-related genes (ECM, SPARC, LOXL۱, MMP۱, MMP۱۴, TLR, ICAM۴, TLR۲) significantly enhance immune-related signaling in PTC. Patients with lymph node metastasis exhibited heightened activity in pathways associated with immunity compared to those without metastasis. The roles of immune checkpoints (PD-L۱, CTLA۴, IDO۱, and HAVCR۲) alongside the signaling pathways of TNF-α and IL-۶/JAT/STAT۳ were emphasized. The classification of PTC patients into three categories—cold (low immune cell density), intermediate (medium immune cell density), and hot (high immune cell density)—indicates that the hot group correlates with a poor prognosis. The hot group exhibited the presence of genes associated with interferon gamma signaling and demonstrated the lowest level of differentiation relative to the cold group. Genes that exhibit a strong correlation with the tumor differentiation of PTC include B۳GNT۹, TSHR, MMP۱۵, LIPG, and CD۲۴. The expression levels of immune evasion-related genes, including CTLA۴, IDO۱, LAG۳, and PDCD۱, were significantly elevated in the hot group compared to the other groups. The HOXD۹ gene serves as a molecular predictor for PTC recurrence. Patients exhibiting high expression of this gene demonstrated a significantly greater incidence of disease recurrence compared to those with low gene expression. Patients with HOXD۹ overexpression exhibited larger tumors and TCF۳ and EZH۲ genes enhance the expression of HOXD۹. Taken together, HOXD۹, TCF۳ and EZH۲ genes are associated with PTCC recurrence. Enrichment analysis of these genes highlighted the NF-kB signaling pathway associated with PTC recurrence. Discussion: Study findings indicate that the NF-κB signal transduction pathway is the primary pathways in PTC patients with HOXD۹ overexpression. The involvement of the NF-κB pathway in the development and recurrence of PTC tumors was established, and it was shown to exhibit resistance to traditional chemotherapy. This pathway is associated with the MAPK-mediated signaling pathway.

کلیدواژه ها:

Papillary thyroid carcinoma ، metastasis ، recurrence