Background: The role of extracellular matrix adhesion components in modulation of the treatment sensitivity of ovarian cancer (OC) cells is not well understood.Methods and Results: Analysis of ovarian cancer TCGA gene expression datasets revealed an inverse correlation between genes involved in cell-cycle progression and extracellular matrix interactions, including laminin-binding receptor integrin β4, a major component of extracellular matrix adhesion. Gene ontology analysis also showed that in patient populations with lowITGB4expression, cell cycle-related programs were activated, while in populations with high expression ofITGB4, the activation of these cell cycle programs was lower. Suppression of proliferation with the CDK4/6 inhibitor Palbociclib stimulated integrin β4 expression and induced protection against Cisplatin in cells naturally expressing low levels of integrin β4. Additionally, ovarian cancer patient-derived organoids showed reduced Cisplatin sensitivity when pretreated with Palbociclib. Our data also showed that integrin β4 overexpression decreased ovarian cancer cell proliferation and at the same time, attenuated Cisplatin response.Conclusions: In summary, our investigations support the idea that integrin β4, and likely its matrix ligands, play critical roles in the regulation of cellular growth and the chemoresistance of ovarian cancer cells.
背景：细胞外基质黏附成分在调控卵巢癌细胞治疗敏感性中的作用尚未明确。 方法与结果：通过对卵巢癌TCGA基因表达数据集的分析，我们发现细胞周期进程相关基因与细胞外基质相互作用相关基因（包括层粘连蛋白受体整合素β4——细胞外基质黏附的主要成分）呈负相关。基因本体分析进一步显示，在ITGB4低表达的患者群体中，细胞周期相关通路被激活；而在ITGB4高表达的群体中，这些细胞周期通路的激活程度较低。使用CDK4/6抑制剂帕博西尼抑制细胞增殖后，可刺激天然低表达整合素β4的细胞中该蛋白的表达，并诱导其对顺铂产生耐药性。此外，经帕博西尼预处理的卵巢癌患者来源类器官对顺铂的敏感性也降低。我们的数据还表明，过表达整合素β4会降低卵巢癌细胞的增殖能力，同时减弱其对顺铂的治疗反应。 结论：综上所述，本研究证实整合素β4及其基质配体在调控卵巢癌细胞生长和化疗耐药性中发挥关键作用。
肿瘤(癌症)患者之家