Protective TGFβ2/SMAD3 axis identified by TWAS in papillary thyroid cancer

Area of Science:

• Endocrinology
• Genetics
• Oncology

Background:

• Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy, with some cases exhibiting aggressive behavior.
• The genetic basis of PTC heterogeneity requires further investigation to identify additional susceptibility genes and regulatory mechanisms.

Purpose of the Study:

• To identify novel susceptibility genes and regulatory mechanisms in papillary thyroid carcinoma.
• To investigate the role of the TGFB2/SMAD3 axis in PTC pathogenesis.

Main Methods:

• Integrated transcriptome-wide association studies (TWAS) with summary-data-based Mendelian randomisation (SMR), joint/conditional testing (JCT), and colocalisation analyses.
• Utilized heterogeneity in dependent instruments (HEIDI) test and gene prioritisation analyses.
• Performed functional experiments in TPC-1 cells to validate TGFβ2/SMAD3 pathway activation.

Main Results:

• TGFB2 and SMAD3 were consistently highlighted as candidate susceptibility genes for PTC, with SMR analysis suggesting protective effects.
• Positive correlation between TGFB2 and SMAD3 expression was confirmed in TCGA-THCA data.
• TGFβ2 treatment in TPC-1 cells inhibited proliferation and migration, induced apoptosis, and caused cell-cycle arrest, indicating activation of the canonical TGFβ signalling pathway via SMAD3 phosphorylation.

Conclusions:

• Convergent evidence from population-based genetic inference and mechanistic validation supports a tumor-suppressive role for the TGFB2/SMAD3 axis in papillary thyroid carcinoma.
• These findings contribute to understanding PTC genetic heterogeneity and suggest potential therapeutic targets.