Abstract：
Osteosarcoma, a highly aggressive bone cancer, often develops resistance to conventional chemotherapeutics, leading to poor prognosis and survival rates. The malignancy and chemoresistance of osteosarcoma pose significant challenges in its treatment, highlighting the critical need for novel therapeutic approaches. Bruton\'s tyrosine kinase (BTK) plays a pivotal role in B-cell development and has been linked to various cancers, including breast, lung, and oral cancers, where it contributes to tumor growth and chemoresistance. Despite its established importance in these malignancies, the impact of BTK on osteosarcoma remains unexplored. Our study delves into the expression levels of BTK in osteosarcoma tissues by data from the GEO and TCGA database, revealing a marked increase in BTK expression compared with primary osteoblasts and a potential correlation with primary site progression. Through our investigations, we identified a subset of osteosarcoma cells, named cis-HOS, which exhibited resistance to cisplatin. These cells displayed characteristics of cancer stem cells (CSCs), demonstrated a higher angiogenesis effect, and had an increased migration ability. Notably, an upregulation of BTK was observed in these cisplatin-resistant cells. The application of ibrutinib, a BTK inhibitor, significantly mitigated these aggressive traits. Our study demonstrates that BTK plays a crucial role in conferring chemoresistance in osteosarcoma. The upregulation of BTK in cisplatin-resistant cells was effectively countered by ibrutinib. These findings underscore the potential of targeting BTK as an effective strategy to overcome chemoresistance in osteosarcoma treatment.
摘要：
骨肉瘤,一种高度侵袭性的骨癌，经常对常规化疗药物产生耐药性，导致不良预后和生存率。骨肉瘤的恶性程度和化疗耐药性对其治疗提出了重大挑战。强调了对新治疗方法的迫切需要。布鲁顿酪氨酸激酶（BTK）在B细胞发育中起关键作用，并与各种癌症有关。包括乳房,肺，和口腔癌，它有助于肿瘤生长和化疗耐药。尽管它在这些恶性肿瘤中已经确立了重要性，BTK对骨肉瘤的影响仍未被探索。我们的研究通过GEO和TCGA数据库的数据深入研究了BTK在骨肉瘤组织中的表达水平。与原发性成骨细胞相比，BTK表达显着增加，并且与原发性部位进展潜在相关。通过我们的调查,我们确定了骨肉瘤细胞的一个子集，命名为顺式居屋，对顺铂表现出耐药性。这些细胞表现出癌症干细胞（CSC）的特征，表现出更高的血管生成效应，并增加了迁移能力。值得注意的是,在这些顺铂耐药细胞中观察到BTK上调。伊布鲁替尼的应用，BTK抑制剂，显著减轻了这些攻击性特征。我们的研究表明，BTK在赋予骨肉瘤化学耐药性中起着至关重要的作用。依鲁替尼有效地对抗了BTK在顺铂耐药细胞中的上调。这些发现强调了靶向BTK作为克服骨肉瘤治疗中化学耐药性的有效策略的潜力。
