Xiong Xiao, Liu Jingfang, Wu Xiaotong, Yao Zhimeng, Meng Yuhua, Liu Shuang, Chen Yexi, Ren Hongzheng, Gao Shegan, Qiu Xiaofu, Zhang Hao
Department of Urology, Guangdong Second Provincial General Hospital, Integrated Chinese and Western Medicine Postdoctoral Research Station, School of Medicine, Jinan University, Guangzhou, China.
State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology and Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, China.
Sci Rep. 2025 Feb 27;15(1):7065. doi: 10.1038/s41598-025-91341-0.
Lung metastasis is the primary cause of breast cancer-related mortality. Protein tyrosine phosphatases such as PTPRO are important in cancer progression. However, the role and underlying mechanisms of PTPRO in breast cancer lung metastasis are largely unknown. The function of PTPRO in breast cancer metastasis was examined in mice with ptpro deficiency driven by the PyMT promoter. The regulatory role of PTPRO in JAK2-YAP activation was tested in cell-based knockdown, overexpression and catalytic-dead mutation assays. Bioinformatics analyses and assays of human cancer specimens and mouse tumour samples were performed to investigate PTPRO-regulated pathways and functions. Ptpro deletion in MMTV-PyMT transgenic mice led to increased lung metastasis. Bioinformatics analyses and subsequent assays of human breast cancer specimens revealed a reverse correlation between PTPRO expression and JAK2-YAP pathway activity. Both in vitro and in vivo data demonstrated that PTPRO inactivates the JAK2-YAP pathway and diminishes the metastatic ability of breast cancer. Analysis of catalytic-dead PTPRO mutant breast cancer cells confirmed that functional PTPRO is a determinant of the activation of the JAK2-YAP pathway and the suppression of breast cancer metastasis. Data from patient, animal and cell-based models collectively demonstrated that PTPRO suppresses breast cancer lung metastasis by inhibiting JAK2-YAP dephosphorylation. Therefore, strengthening PTPRO or targeting PTPRO-mediated pathways could be potential strategies for inhibiting breast cancer lung metastasis.
肺转移是乳腺癌相关死亡的主要原因。蛋白酪氨酸磷酸酶如PTPRO在癌症进展中起重要作用。然而，PTPRO在乳腺癌肺转移中的作用及潜在机制在很大程度上尚不清楚。在由PyMT启动子驱动的ptpro缺陷小鼠中研究了PTPRO在乳腺癌转移中的功能。在基于细胞的敲低、过表达和催化失活突变试验中测试了PTPRO对JAK2-YAP激活的调节作用。进行了生物信息学分析以及对人类癌症标本和小鼠肿瘤样本的检测，以研究PTPRO调节的途径和功能。MMTV-PyMT转基因小鼠中的Ptpro缺失导致肺转移增加。对人类乳腺癌标本的生物信息学分析及后续检测显示PTPRO表达与JAK2-YAP通路活性呈负相关。体外和体内数据均表明，PTPRO可使JAK2-YAP通路失活，并降低乳腺癌的转移能力。对催化失活的PTPRO突变型乳腺癌细胞的分析证实，功能性PTPRO是JAK2-YAP通路激活和抑制乳腺癌转移的决定因素。来自患者、动物和细胞模型的数据共同表明，PTPRO通过抑制JAK2-YAP去磷酸化来抑制乳腺癌肺转移。因此，增强PTPRO或靶向PTPRO介导的途径可能是抑制乳腺癌肺转移的潜在策略。
