Ruan Xianhui, Huang Yue, Zeng Yu, Zhao Zhenhao, Tao Mei, Zhao Zewei, Wang Yuqi, Xu Guangwei, Zhang Wei, Yu Jialong, Luo Wei, Wei Songfeng, Li Xichuan, Gao Ming, Yu Yang, Li Peng, Zheng Xiangqian
Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Nankai University, Tianjin, China.
Cell Death Dis. 2025 Jul 1;16(1):474. doi: 10.1038/s41419-025-07797-5.
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.
Y染色体性别决定区(SRY)-盒(SOX)家族在肿瘤发生和癌症进展中起关键作用。然而,SOX12在甲状腺乳头状癌(PTC)转移中的具体功能仍有待研究。在本研究中,我们分析了单细胞和批量RNA测序(RNA-seq)数据集,结果显示PTC中SOX12显著上调,这与PTC患者的不良预后相关。功能实验表明,SOX12过表达促进了PTC细胞的转移,而SOX12的下调则显著降低了PTC的侵袭性。通过整合RNA-seq、CUT&Tag和免疫沉淀质谱(IP-MS),我们发现SOX12直接上调YBX1的表达,并将其招募至LDHA启动子,从而导致TGF-β信号通路的激活。至关重要的是,敲低LDHA可挽救SOX12/YBX1介导的TGF-β信号激活,并抑制PTC细胞的迁移和侵袭。此外,我们还证明,在临床PTC样本中,SOX12的表达与YBX1和LDHA的表达水平呈正相关。综上所述,这些结果揭示了SOX12-YBX1-LDHA信号轴与PTC转移之间的关键联系,并表明靶向该信号节点可能是对抗PTC转移的一种有前景的替代治疗策略。
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