DLC1 tumor suppressor gene inhibits migration and invasion of multiple myeloma cells through RhoA GTPase pathway.
DLC1 tumor suppressor gene inhibits migration and invasion of multiple myeloma cells through RhoA GTPase pathway.
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DLC1是一种肿瘤抑制基因，编码RhoGTPase激活蛋白，由于表观遗传修饰或基因组缺失，在各种实体肿瘤和血液系统恶性肿瘤中反复下调或沉默。在这里，我们在44个多发性骨髓瘤(MM)细胞系中发现43个DLC-1启动子高甲基化，导致41个样本中DLC-1表达下调或沉默。肿瘤特异性甲基化的高频率和DLC1表达的减弱或沉默可作为MM的独立诊断指标。去甲基化和乙酰化药物联合治疗可显著上调DLC1的表达并抑制MM细胞的增殖。用含DLC1基因的腺病毒载体转导两株启动子完全甲基化而不表达DLC1的细胞系。在这两种细胞系中，DLC1的重新表达抑制了骨髓瘤细胞的侵袭和迁移，降低了RhoA的活性，并导致了肌动蛋白细胞骨架的重组。这些结果为DLC1在血液病中的抗增殖作用提供了第一个证据，并暗示RhoA途径在抑制MM的迁移和侵袭中起作用。考虑到骨髓瘤细胞对DLC-1功能重新激活的敏感性，DLC-1介导的通路的分子靶向治疗以及表观遗传治疗具有潜在的前景。
DLC1, a tumor suppressor gene that encodes a RhoGTPase-activating protein, is recurrently downregulated or silenced in various solid tumors and hematological malignancies due to epigenetic modifications or genomic deletion. Here, we identified DLC-1 promoter hypermethylation in 43 out of 44 multiple myeloma (MM) cell lines, which resulted in downregulation or silencing of DLC1 in 41 samples. High frequency of tumor-specific methylation and attenuation or silencing of DLC1 expression could serve as an independent diagnostic marker for MM. Combined treatment with demethylating and acetylating agents significantly elevated the expression of DLC1 and suppressed MM cell proliferation. Two cell lines exhibiting complete promoter methylation and absence of DLC1 expression were transduced by an adenoviral vector containing DLC1 cDNA. In both cell lines reexpression of DLC1 inhibited myeloma cell invasion and migration, reduced RhoA activity and resulted in reorganization of actin cytoskeleton. These results provide the first evidence for antiproliferative effect of DLC1 in a hematological cancer and implicate RhoA pathway in suppression of MM migration and invasion. Given the myeloma cells sensitivity to reactivation of DLC-1 function, the potential for molecular targeted therapy of DLC-1 mediated pathways as well as epigenetic therapies hold prospects.
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影响因子：
20.3
作者：
Qiang, YW;Yao, L;Rudikoff, S
通讯作者：
Rudikoff, S
影响因子：
10.5
作者：
Lahoz, Aurelia;Hall, Alan
通讯作者：
Hall, Alan
DOI：
10.1073/pnas.0703033104
发表时间：
2007-05-22
影响因子：
11.1
作者：
Qian, Xiaolan;Li, Guorong;Lowy, Douglas R.
通讯作者：
Lowy, Douglas R.
影响因子：
3.7
作者：
Gabrea, Ana;Martelli, Maria Luisa;Qi, Ying;Roschke, Anna;Barlogie, Bart;Shaughnessy, John D., Jr.;Sawyer, Jeffrey R.;Kuehl, W. Michael
通讯作者：
Kuehl, W. Michael
影响因子：
20.3
作者：
Qiang, YW;Walsh, K;Rudikoff, S
通讯作者：
Rudikoff, S