Peng Jie, Lv Liang, Zhou Yuqian, Wang Xuehong, Hu Changmei
Department of Haematology, Xiangya Hospital, Central South University, Changsha, China.
Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, China.
Cancer Sci. 2025 Mar;116(3):808-823. doi: 10.1111/cas.16420. Epub 2024 Dec 12.
The abnormal expression of PHAX was observed in esophageal cancer, however, its specific function and mechanism remain to be further elucidated. We demonstrated that PHAX, LIN28B, and PBX3 were upregulated in esophageal cancer, while TET2 was downregulated. Elevated PHAX correlated with adverse outcomes among esophageal cancer patients. PHAX or PBX3 knockdown not only inhibited esophageal cancer cell proliferation, and promoted apoptosis and autophagy in vitro, but it also repressed tumor growth and lung metastasis in mice. Mechanically, PHAX stabilized PBX3 mRNA through interacting with LIN28B. PBX3 directly bound to the TET2 promoter region and inhibited its expression. In conclusion, PHAX directly bound to LIN28B and enhanced LIN28B-mediated stabilization of PBX3 mRNA, leading to upregulation of PBX3. PBX3 then transcriptionally repressed TET2 expression to promote esophageal cancer cell proliferation, and suppress apoptosis and autophagy. Targeting this signaling cascade could represent a promising therapeutic strategy for esophageal cancer.
在食管癌中观察到PHAX的异常表达，然而，其具体功能和机制仍有待进一步阐明。我们证明，在食管癌中PHAX、LIN28B和PBX3上调，而TET2下调。食管癌患者中PHAX升高与不良预后相关。敲低PHAX或PBX3不仅在体外抑制食管癌细胞增殖，促进细胞凋亡和自噬，还能抑制小鼠肿瘤生长和肺转移。机制上，PHAX通过与LIN28B相互作用来稳定PBX3 mRNA。PBX3直接结合到TET2启动子区域并抑制其表达。总之，PHAX直接结合LIN28B并增强LIN28B介导的PBX3 mRNA稳定性，导致PBX3上调。然后PBX3转录抑制TET2表达，以促进食管癌细胞增殖，并抑制细胞凋亡和自噬。靶向这一信号级联可能是一种有前景的食管癌治疗策略。
