Katsuta Eriko, Sawant Dessai Abhisha, Ebos John Ml, Yan Li, Ouchi Toru, Takabe Kazuaki
Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center Buffalo, NY, USA.
Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center Buffalo, NY, USA.
Am J Cancer Res. 2022 Feb 15;12(2):793-804. eCollection 2022.
The phosphorylated histone variant, γ-H2AX, is known to play a key role in DNA damage repair. However, the clinical significance of H2AX mRNA expression in breast cancer remains unclear. Utilizing a bioinformatical approach, a total of 3594 breast cancer patients with clinical and transcriptomic data were investigated. Bioinformatical analysis showed that high expression of H2AX is associated with worse disease-free, disease-specific, and overall survival consistently in two independent cohorts. High H2AX expressing tumors were associated with upregulated DNA repair gene sets. Although H2AX was not predictive of chemotherapy response, it was significantly downregulated after effective chemotherapy or radio-chemotherapy. Notably, tumors with high H2AX expression were enriched for DNA replication and MYC targets gene sets, and associated with increased MKI67 expression, suggesting alterations in cell proliferation machinery. H2AX knockdown cells showed decreased cell proliferation as compared to the control cells. Finally, H2AX mRNA expression was higher in the metastatic clones as compared to the parental cells and in the metastatic tumors as compared to the primary tumors in patients, with higher H2AX mRNA expression found in advanced stage cancer patients. In conclusion, high H2AX mRNA expression is associated with increased DNA repair, cell proliferation, metastasis, and worse survival in breast cancer patients.
磷酸化组蛋白变体γ-H2AX在DNA损伤修复中发挥关键作用。然而，H2AX mRNA表达在乳腺癌中的临床意义仍不明确。利用生物信息学方法，对3594例有临床和转录组数据的乳腺癌患者进行了研究。生物信息学分析表明，在两个独立队列中，H2AX的高表达始终与无病生存期、疾病特异性生存期和总生存期较差相关。高表达H2AX的肿瘤与上调的DNA修复基因集相关。虽然H2AX不能预测化疗反应，但在有效的化疗或放化疗后其表达显著下调。值得注意的是，高表达H2AX的肿瘤富含DNA复制和MYC靶基因集，并与MKI67表达增加相关，提示细胞增殖机制发生改变。与对照细胞相比，H2AX敲低的细胞显示出细胞增殖减少。最后，与亲本细胞相比，转移克隆中的H2AX mRNA表达更高，与患者的原发肿瘤相比，转移瘤中的H2AX mRNA表达更高，晚期癌症患者中H2AX mRNA表达更高。总之，H2AX mRNA高表达与乳腺癌患者DNA修复增加、细胞增殖、转移及较差的生存率相关。
