Qin S, Yan J, Xin J
Department of Thyroid Surgery, Nantong Haimen People's Hospital, Nantong, Jiangsu, 226100, China.
Department of the Operating Room, Huaian Hospital of Huaian City, Huaian Cancer Hospital, Huaian, Jiangsu, 223200, China.
J Physiol Pharmacol. 2025 Jun;76(3). doi: 10.26402/jpp.2025.3.08. Epub 2025 Jul 16.
Breast cancer remains a significant global health concern, with its molecular intricacies and the mechanistic role of tissue inhibitor of metalloproteinases-1 (TIMP1) still poorly understood. This study employed an integrated approach combining bioinformatic analyses and primary experimental validations to discover the complexities surrounding TIMP1 in breast cancer. Bioinformatic tools such as pan-cancer view, mRNA expression analysis, immune infiltrations, pathway enrichment, and functional annotations provided a clear perspective on TIMP1 in breast cancer. Gene expression by qPCR analysis for TIMP1 were conducted in MCF-7 and MDA-MB-231 and T47D cells and compared to normal breast cells, MCF-10A. Bioinformatic platform, The University of Alabama at Birmingham Cancer (UALCAN) data analysis underscored the diagnostic relevance of TIMP1, showing its upregulated mRNA expression across different stages and metastatic properties. Notably, the impact of breast cancer on immune cells was explored, revealing a direct influence of TIMP1 on CD4, CD8, and B cells, with strong correlations were observed. Kaplan-Meier (KM) survival analysis revealed that high TIMP1 expression correlates with poor prognosis in breast cancer patients, reinforcing its oncogenic potential. Furthermore, immunohistochemistry supported these findings, and protein-protein interaction analysis through STRING and CYTOSCAPE identified interconnected genes linked to TIMP1 in breast cancer. Enriched pathway analysis using KEGG pathways unveiled the potential involvement of TIMP1 in the phosphatidylinositol 3-kinases (PI3K) pathway and cell cycle regulation, further substantiating its oncogenic role. Experimental validation through siRNA silencing TIMP1 reduces cell growth and promotes G1 phase cell cycle arrest in MDA-MB-231 cells. In conclusion, this comprehensive study suggests that targeting TIMP1 in breast cancer could present a promising avenue for therapeutic development, highlighting its potential as a crucial player in the molecular landscape of breast cancer progression.
乳腺癌仍然是一个重大的全球健康问题，其分子复杂性以及金属蛋白酶组织抑制剂-1（TIMP1）的作用机制仍未得到充分了解。本研究采用了生物信息学分析和初步实验验证相结合的综合方法，以揭示乳腺癌中TIMP1周围的复杂性。诸如泛癌视图、mRNA表达分析、免疫浸润、通路富集和功能注释等生物信息学工具为乳腺癌中的TIMP1提供了清晰的视角。通过qPCR分析在MCF-7、MDA-MB-231和T47D细胞中检测TIMP1的基因表达，并与正常乳腺细胞MCF-10A进行比较。生物信息学平台阿拉巴马大学伯明翰分校癌症（UALCAN）数据分析强调了TIMP1的诊断相关性，显示其在不同阶段和转移特性中的mRNA表达上调。值得注意的是，研究了乳腺癌对免疫细胞的影响，发现TIMP1对CD4、CD8和B细胞有直接影响，并观察到强相关性。Kaplan-Meier（KM）生存分析表明，TIMP1高表达与乳腺癌患者的不良预后相关，强化了其致癌潜力。此外，免疫组织化学支持了这些发现，通过STRING和CYTOSCAPE进行的蛋白质-蛋白质相互作用分析确定了与乳腺癌中TIMP1相关的相互连接基因。使用KEGG通路进行的富集通路分析揭示了TIMP1可能参与磷脂酰肌醇3激酶（PI3K）通路和细胞周期调控，进一步证实了其致癌作用。通过siRNA沉默TIMP1的实验验证降低了MDA-MB-231细胞的生长并促进了G1期细胞周期停滞。总之，这项综合研究表明，在乳腺癌中靶向TIMP1可能为治疗开发提供一条有前景的途径，突出了其作为乳腺癌进展分子格局中关键参与者的潜力。
