Bmi-1 cooperates with H-ras to transform human mammary epithelial cells via Dysregulation of multiple growth-regulatory pathways
Bmi-1 cooperates with H-ras to transform human mammary epithelial cells via Dysregulation of multiple growth-regulatory pathways
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DOI：
10.1158/0008-5472.can-07-1636
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发表时间：
2007-11-01
期刊：
影响因子：
11.2
通讯作者：
Dimri, Goberdhan P.
中科院分区：
文献类型：
--
作者：
Datta, Sonal;Hoenerhoff, Mark J.;Dimri, Goberdhan P.
Bmi-I的高表达与许多癌症相关，包括乳腺癌。在这里，我们研究了Bmi-1在MCF 10A细胞中的致癌潜力，MCF 10A细胞是一种自发永生化的非转化株人乳腺上皮细胞（HMEC）。在MCF 10A细胞中单独的Bmi-1过表达不导致致癌转化。然而，Bmi-1与活化的H-Ras（RasG 12 V）共过表达导致MCF 10A细胞在体外的有效转化。尽管早期传代的表达H-Ras的MCF 10A细胞没有转化，但晚期传代的表达H-Ras的细胞在体外表现出转化的特征。早代和晚代H-Ras表达细胞的H-Ras和Ki-67（增殖标志物）表达水平也不同。早期传代的H-Ras表达细胞亚群表现出高Ras表达，Ki-67阴性，而大多数晚期传代的H-Ras表达细胞表达低水平的Ras，Ki-67阳性。注射晚期传代的H-Ras表达细胞在严重的联合inummodeficient小鼠形成癌与平滑肌瘤，血管瘤，肥大细胞成分，这些肿瘤是相当不同的诱导的晚期传代细胞共同过度表达Bmi-1和H-Ras，形成低分化癌与梭形细胞的功能。Bmi-1和H-Ras在MCF 10A细胞中的共过表达也诱导了上皮向间充质转化的特征。重要的是，Bmi-1抑制衰老并允许表达高水平Ras的细胞增殖。对各种生长调节途径的研究表明，Bmi-1过表达与H-Ras一起通过p16（INK 4a）非依赖性机制对多种生长调节途径的失调促进HMEC转化和乳腺癌发生。
Elevated expression of Bmi-I is associated with many cancers, including breast cancer. Here, we examined the oncogenic potential of Bmi-1 in MCF10A cells, a spontaneously immortalized, nontransformed strain of human mammary epithelial cells (HMEC). Bmi-1 overexpression alone in MCF10A cells did not result in oncogenic transformation. However, Bmi-1 co-overexpression with activated H-Ras (RasG12V) resulted in efficient transformation of MCF10A cells in vitro. Although early-passage H-Ras-expressing MCF10A cells were not transformed, late-passage H-Ras-expressing cells exhibited features of transformation in vitro. Early- and late-passage H-Ras-expressing cells also differed in levels of expression of H-Ras and Ki-67, a marker of proliferation. Subsets of early-passage H-Ras-expressing cells exhibited high Ras expression and were negative for Ki-67, whereas most late-passage H-Ras-expressing cells expressed low levels of Ras and were Ki-67 positive. Injection of late-passage H-Ras-expressing cells in severe combined inummodeficient mice formed carcinomas with leiomatous, hemangiomatous, and mast cell components; these tumors were quite distinct from those induced by late-passage cells co-overexpressing Bmi-1 and H-Ras, which formed poorly differentiated carcinomas with spindle cell features. Bmi-1 and H-Ras co-overexpression in MCF10A cells also induced features of epithelial-to-mesenchymal transition. Importantly, Bmi-1 inhibited senescence and permitted proliferation of cells expressing high levels of Ras. Examination of various growth-regulatory pathways suggested that Bmi-1 overexpression together with H-Ras promotes HMEC transformation and breast oncogenesis by deregulation of multiple growth-regulatory pathways by p16(INK4a)-independent mechanisms.