Department of Cellular Therapy and Cancer Research, King Abdullah International Medical Research Center, Jeddah, Saudi Arabia.
King Saud bin Abdulaziz University for Health Sciences, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia.
J Cell Mol Med. 2022 Oct;26(19):4959-4973. doi: 10.1111/jcmm.17512. Epub 2022 Sep 3.
Human Epidermal Growth Factor Receptor 2 (HER2) overexpression is considered one of the interesting prognostic biomarkers in bladder cancer. However, the mechanism of bladder cancer development in relation to HER2 status remains to be elucidated. In this study, we investigated HER2-Ataxia telangiectasia mutated (ATM) kinase interaction and their impact on patient survival and cancer aggressiveness. Using the Cancer Genome Atlas (TCGA) cohorts, we demonstrated that ATM expression (protein/mRNA) is increased in HER2 deficient compared with proficient HER2 patients. This finding was then validated using the Gene Expression Omnibus database (GEO). Correlation analysis (using low expression vs high expression as a discriminator) revealed a significant association of ATM low and HER2 high status with several clinicopathological variables such as high tumour grade, late disease stage and tumour shape. Kaplan-Meier survival analysis indicated that ATM low and HER2 high is a powerful prognosticator of both overall survival (OS) and disease-free survival (DFS). Furthermore, using bioinformatics and protein/protein interaction analyses, we identified 66 putative overlapping proteins with direct link between HER2 and ATM most of which are functionally involved in transcription regulation, apoptotic process and cell proliferation. Interestingly, the results showed that these proteins are strongly linked with PI3K-Akt pathway, p53 pathway and microRNAs in cancer. Altogether, our data pinpoint an important biological role of the interconnection between HER2 and ATM. The latter appear to be an independent prognostic biomarker and may serve as targets to develop novel combination therapies to improve the outcome of patients with bladder cancer.
人类表皮生长因子受体 2（HER2）过表达被认为是膀胱癌有意义的预后生物标志物之一。然而，与 HER2 状态相关的膀胱癌发展机制仍有待阐明。在这项研究中，我们研究了 HER2-共济失调毛细血管扩张突变（ATM）激酶相互作用及其对患者生存和癌症侵袭性的影响。使用癌症基因组图谱（TCGA）队列，我们证明与 HER2 功能正常的患者相比，HER2 缺陷的患者中 ATM 表达（蛋白/信使 RNA）增加。这一发现随后使用基因表达综合数据库（GEO）进行了验证。相关性分析（使用低表达与高表达作为判别器）显示，ATM 低表达和 HER2 高表达与肿瘤分级高、疾病晚期和肿瘤形状等多个临床病理变量显著相关。Kaplan-Meier 生存分析表明，ATM 低表达和 HER2 高表达是总生存（OS）和无病生存（DFS）的有力预后指标。此外，我们使用生物信息学和蛋白质/蛋白质相互作用分析，确定了 66 个具有 HER2 和 ATM 之间直接联系的假定重叠蛋白，其中大多数在转录调节、凋亡过程和细胞增殖中具有功能。有趣的是，结果表明这些蛋白与癌症中的 PI3K-Akt 通路、p53 通路和 microRNAs 密切相关。总之，我们的数据指出了 HER2 和 ATM 之间相互联系的重要生物学作用。后者似乎是一个独立的预后生物标志物，并可能作为靶点，开发新的联合治疗方法，以改善膀胱癌患者的预后。
