GOLPH3 drives papillary thyroid carcinoma progression by activating the TGF-β signaling pathway

The global incidence of thyroid cancer is increasing, with papillary thyroid carcinoma (PTC) being the most common subtype. While many patients have favorable prognoses, a significant subset develops aggressive, therapy-resistant disease, underscoring the critical need for identifying novel molecular targets. Golgi phosphoprotein 3 (GOLPH3) has emerged as a potential oncogene across various solid tumors, but its precise functional role and mechanistic contributions to PTC progression have remained largely undefined. This study aimed to clarify GOLPH3's biological function in PTC and investigate its oncogenic effects through the TGF-β signaling pathway.

Researchers investigated GOLPH3's role in PTC using in vitro cell models. They first determined GOLPH3 expression levels in PTC cells via qPCR and Western blot (WB). To understand its functional impact, GOLPH3 was either knocked down or overexpressed in PTC cells. Cell viability was assessed using CCK-8 assays, apoptosis levels by flow cytometry, and migration/invasion capabilities through Transwell assays. Senescence was quantified via β-galactosidase staining. KEGG analysis identified enriched signaling pathways. The study also used WB to detect key markers of the TGF-β signaling pathway (TGF-β1, SMAD2, p-SMAD2, p-SMAD3, SMAD3) and EMT markers (E-cadherin, N-cadherin, Snail). The TGF-β pathway inhibitor LY2109761 was used to reverse effects induced by GOLPH3 overexpression.

GOLPH3 expression was consistently upregulated in papillary thyroid carcinoma (PTC) cells compared to controls. Functional studies demonstrated that GOLPH3 knockdown significantly mitigated several malignant phenotypes in cancer cells. Specifically, knockdown reduced cell viability, invasiveness, and motility, while simultaneously elevating the apoptosis rate and increasing the proportion of senescent cells. KEGG analysis revealed that GOLPH3 was significantly enriched in the TGF-β signaling pathway, indicating a strong mechanistic link. Furthermore, GOLPH3 knockdown was shown to inhibit the TGF-β pathway and block the epithelial-mesenchymal transition (EMT) process, a key driver of metastasis. Conversely, GOLPH3 overexpression actively promoted PTC progression by activating this same pathway. > The TGF-β pathway inhibitor LY2109761 effectively reversed the pro-tumorigenic effects induced by GOLPH3 overexpression, confirming the pathway's critical role in GOLPH3-mediated malignancy. These findings collectively establish GOLPH3 as a pivotal driver of PTC malignancy through its activation of the TGF-β signaling pathway.