The SOX12-YBX1-LDHA signaling axis drives metastasis in papillary thyroid carcinoma

TL;DR

This study identifies a new signaling pathway involving SOX12, YBX1, and LDHA that promotes the spread of papillary thyroid cancer and suggests targeting this pathway as a potential treatment.

Contribution

The study reveals a novel SOX12-YBX1-LDHA signaling axis that drives metastasis in papillary thyroid carcinoma.

Findings

SOX12 is significantly upregulated in papillary thyroid carcinoma and linked to poor patient outcomes.

SOX12 promotes cancer cell metastasis by upregulating YBX1 and activating the TGF-β pathway through LDHA.

LDHA knockdown inhibits SOX12/YBX1-driven TGF-β signaling and reduces cancer cell migration and invasion.

Abstract

The sex-determining region Y (SRY)-box (SOX) family plays crucial roles in carcinogenesis and cancer progression. However, the precise function of SOX12 in papillary thyroid carcinoma (PTC) metastasis remains to be investigated. In this study, we analyzed single-cell and bulk RNA sequencing (RNA-seq) datasets and demonstrated significant upregulation of SOX12 in PTC, which is associated with poor prognosis in PTC patients. Functional assays demonstrated that SOX12 overexpression promoted the metastasis of PTC cells, whereas the downregulation of SOX12 markedly reduced the aggressiveness of PTC. By integrating RNA-seq, CUT&Tag, and immunoprecipitation mass spectrometry (IP-MS), we found that SOX12 directly upregulated YBX1 expression and recruited it to the LDHA promoter, thus leading to activation of the TGF-β signaling pathway. Crucially, LDHA knockdown rescued SOX12/YBX1-mediated TGF-β signaling activation and inhibited the migration and invasion of PTC cells. Furthermore, we demonstrated that SOX12 expression is positively correlated with YBX1 and LDHA expression levels in clinical PTC samples. Taken together, these results reveal a critical link between the SOX12-YBX1-LDHA signaling axis and PTC metastasis and suggest that targeting of this signaling node may be a promising alternative therapeutic strategy to combat PTC metastasis.

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