PDF(Pubmed)
Abstract：
Breast cancer is the most common malignant cancer in women worldwide. Cancer metastasis is the major cause of cancer-related deaths. BCKDK is associated with various diseases, including proliferation, migration, and invasion in multiple types of human cancers. However, the relevance of BCKDK to the development and progression of breast cancers and its function is unclear. This study found that BCKDK was overexpressed in breast cancer, associated with poor prognosis, and implicated in tumor metastasis. The downregulation of BCKDK expression inhibited the migration of human breast cancer cells in vitro and diminished lung metastasis in vivo. BCKDK perturbed the cadherin-catenin complex at the adherens junctions (AJs) and assembled focal adhesions (FAs) onto the extracellular matrix, thereby promoting the directed migration of breast cancer cells. We observed that BCKDK acted as a conserved regulator of the ubiquitination of cytoskeletal protein talin1 and the activation of the FAK/MAPK pathway. Further studies revealed that BCKDK inhibited the binding of talin1 to E3 ubiquitin ligase-TRIM21, leading to the decreased ubiquitination/degradation of talin1. In conclusion, identifying BCKDK as a biomarker for breast cancer metastasis facilitated further research on diagnostic biomarkers. Elucidating the mechanism by which BCKDK exerted its biological effect could provide a new theoretical basis for developing new markers for breast cancer metastasis and contribute to developing new therapies for the clinical treatment of breast cancer patients.
摘要：
乳腺癌是全球女性最常见的恶性肿瘤。癌症转移是癌症相关死亡的主要原因。BCKDK与多种疾病相关,包括扩散，迁移,和入侵多种类型的人类癌症。然而,BCKDK与乳腺癌发生发展及其功能的相关性尚不清楚.这项研究发现，BCKDK在乳腺癌中过度表达，与不良预后相关，并与肿瘤转移有关。BCKDK表达的下调在体外抑制了人乳腺癌细胞的迁移，并在体内减少了肺转移。BCKDK扰乱了粘附连接（AJ）处的钙粘蛋白-连环蛋白复合物，并将粘着斑（FA）组装到细胞外基质上，从而促进乳腺癌细胞的定向迁移。我们观察到BCKDK是细胞骨架蛋白talin1泛素化和FAK/MAPK通路激活的保守调节因子。进一步的研究表明，BCKDK抑制滑石1与E3泛素连接酶-TRIM21的结合，导致滑石1的泛素化/降解减少。总之,鉴定BCKDK作为乳腺癌转移的生物标志物有助于进一步研究诊断性生物标志物。阐明BCKDK发挥其生物学效应的机制,可为开发乳腺癌转移新标志物提供新的理论依据,为临床治疗乳腺癌患者提供新的治疗方法。
