Yi-Chen Lv, Jie-Hao Zhou, Tie-Feng Shi, Yun-Fu Cui
These findings identify PLEC as a candidate molecule associated with aggressive PTC phenotypes and provide preliminary evidence supporting its biological relevance, although larger independent cohorts are required to validate its clinical significance.
OBJECTIVE: This study aimed to characterize molecular subtypes of Papillary thyroid carcinoma (PTC) and identify novel therapeutic targets and potential therapeutic compounds.
METHODS: We performed integrative analysis of TCGA data, including consensus clustering, mutational profiling, copy number variation (CNV) analysis, functional enrichment (GO and GSEA), and immune microenvironment assessment (CIBERSORT). Validation utilized GEO datasets. The biological function of Plectin (PLEC) was investigated through expression analysis (TCGA, GEO, qRT-PCR and IHC), association with clinical parameters, and functional experiments such as siRNA knockdown or overexpression of PLEC in TPC-1 and B-CPAP cell lines assessing cell growth, proliferation, apoptosis, and migration both in vitro and in vivo. Drug candidates targeting PLEC were screened (DGIdb and DrugMap) and validated via molecular docking, dynamics simulations (RMSD, RMSF and Rg), and rescue experiments. Favorable biosafety was tested by ELISA kits and H&E staining.
RESULTS: Consensus clustering revealed four stable molecular subtypes (A1-A4) with distinct mutational landscapes (e.g., prevalent BRAF mutations (59%), subtype-specific alterations in CAND1/PCDH11X (A1) and PTEN (A4)), CNV gains (e.g., A1: 2p16.1/19p13.3), and immune features (A3 enriched in immune pathways). PLEC is up-regulated in PTC tissues compared with non-tumor thyroid tissues and was associated with lymph node metastasis, histological type, and residual tumor status in TCGA-THCA. Knockdown of PLEC significantly suppressed PTC cell growth, proliferation, and migration while inducing apoptosis. Whereas PLEC overexpression partially reversed these phenotypes. Among FDA-approved drugs predicted to target PLEC, Troglitazone exhibited the lowest binding affinity (-7.5 kcal/mol). Troglitazone's anti-tumor effects (inhibiting proliferation/migration, inducing apoptosis) were partially reversed by PLEC overexpression, suggesting that PLEC may participate in Troglitazone-associated anti-PTC effects.
CONCLUSION: These findings identify PLEC as a candidate molecule associated with aggressive PTC phenotypes and provide preliminary evidence supporting its biological relevance, although larger independent cohorts are required to validate its clinical significance.