Integrin β7-mediated regulation of multiple myeloma cell adhesion, migration, and invasion
Integrin β7-mediated regulation of multiple myeloma cell adhesion, migration, and invasion
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DOI：
10.1182/blood-2010-06-292243
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发表时间：
2011-06-09
期刊：
影响因子：
20.3
通讯作者：
Bahlis, Nizar J.
中科院分区：
文献类型：
--
作者：
Neri, Paola;Ren, Li;Bahlis, Nizar J.
在多发性骨髓瘤（MM）细胞中检测到整合素-β 7（ITGB 7）mRNA，其存在与MAF基因激活相关。虽然几个整合素家族成员参与MM-造口细胞相互作用已被充分证明，但MM中整合素β 7调节的特定生物学功能在很大程度上是未知的。在临床上，我们已经将MM中整合素β 7的表达与自体干细胞移植和硼替佐米挽救治疗后的不良生存结局相关。在功能上，我们已经发现ITGB 7的shRNA介导的沉默减少MM细胞与细胞外基质元件（纤连蛋白、E-钙粘蛋白）的粘附，并逆转细胞粘附介导的耐药性（CAM-DR），使它们对硼替佐米和美法仑敏感。此外，ITGB 7沉默消除了MM细胞响应于SDF 1 α梯度的transwell迁移，降低了异种移植肿瘤中的血管密度，并改变了MM细胞体内归巢到BM中。从机制上讲，ITGB 7敲低抑制了粘着斑激酶（FAK）和Src磷酸化、Rac 1活化和SUMO化，减少了MM-BM干细胞共培养物中VEGF的产生，并减弱了p65-NF-κ B活性。我们的研究结果支持整合素β 7在MM细胞粘附、迁移和BM归巢中的作用，并为靶向该分子的新型治疗方法铺平了道路。（血。2011;117（23）：6202-6213）
Integrin-beta 7 (ITGB7) mRNA is detected in multiple myeloma (MM) cells and its presence is correlated with MAF gene activation. Although the involvement of several integrin family members in MM-stoma cell interaction is well documented, the specific biologic functions regulated by integrin-beta 7 in MM are largely unknown. Clinically, we have correlated integrin-beta 7 expression in MM with poor survival outcomes post autologous stem cell transplantation and postsalvage therapy with bortezomib. Functionally, we have found that shRNA-mediated silencing of ITGB7 reduces MM-cell adhesion to extracellular matrix elements (fibronectin, E-cadherin) and reverses cell-adhesion-mediated drug resistance (CAM-DR) sensitizing them to bortezomib and melphalan. In addition, ITGB7 silencing abrogated MM-cell transwell migration in response to SDF1 alpha gradients, reduced vessel density in xenografted tumors, and altered MM cells in vivo homing into the BM. Mechanistically, ITGB7 knockdown inhibited focal adhesion kinase (FAK) and Src phosphorylation, Rac1 activation, and SUMOylation, reduced VEGF production in MM-BM stem cell cocultures and attenuated p65-NF-kappa B activity. Our findings support a role for integrin-beta 7 in MM-cell adhesion, migration, and BM homing, and pave the way for a novel therapeutic approach targeting this molecule. (Blood. 2011;117(23):6202-6213)