p53是人類重要的腫瘤抑制基因，正常p53的生物功能好似“基因組衛(wèi)士(Guardian of the Genome)”,在G1期檢查DNA損傷點，監(jiān)視基因組的完整性。當(dāng)基因組遭受損傷時，p53蛋白可阻止DNA復(fù)制，以提供足夠的時間使損傷DNA修復(fù)；如果修復(fù)失敗，p53蛋白則會引發(fā)細(xì)胞凋亡。當(dāng)p53基因的兩個拷貝都發(fā)生突變時，細(xì)胞的增殖會失去控制，從而導(dǎo)致細(xì)胞癌變。
近日來自薩克生物研究學(xué)院和普林斯頓大學(xué)高級研究所的研究人員在共同合作的一項研究中發(fā)現(xiàn)p53還可抑制癌細(xì)胞向更富于侵襲性的干細(xì)胞樣狀態(tài)轉(zhuǎn)化。研究人員根據(jù)p53的這個新功能將其稱之為“防止基因組重編程的衛(wèi)士（Guardian against Genome Reprogramming）”。研究論文發(fā)表在本周的 PNAS 雜志上。
“我們的研究結(jié)果表明與干細(xì)胞相似的癌細(xì)胞并不是早期腫瘤的組成部分，而是在腫瘤發(fā)生的后期隨著p53功能的喪失才出現(xiàn)的，“論文的共同作者、博士后研究人員Benjamin T. Spike說：“腫瘤異質(zhì)性有可能是由于不斷增長的基因組不穩(wěn)定性和與干細(xì)胞樣表型相關(guān)的表觀遺傳不穩(wěn)定性共同作用所致。”
Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1017001108
Inactivation of p53 in breast cancers correlates with stem cell transcriptional signatures
Hideaki Mizunoa,b,1, Benjamin T. Spikec,1, Geoffrey M. Wahlc, and Arnold J. Levinea,d,2
Abstract
Breast cancer comprises a heterogeneous set of diseases distinguishable from one another by pathologic presentation and molecular signatures. However, each breast cancer subtype is also heterogeneous. Some of the heterogeneity may be attributable to genetic instability, but recent data emphasize that developmental plasticity may also contribute. The p53 tumor suppressor could constitute a nodal control point underlying both sources of heterogeneity because it is frequently inactivated during malignant progression and has recently been shown to function as a potent barrier preventing fully differentiated cells from reverting to pluripotent stem cells after expression of appropriate oncogenes. Using archival microarray datasets, we tested the hypothesis that a p53 mutation could allow cells within a tumor to acquire a stem cell-like state by looking for coordinate expression of stem cell identity genes. We show that breast and lung cancers with p53 mutations do exhibit stem cell-like transcriptional patterns. Such tumors were also depleted for differentiation genes regulated by the polycomb repressor complex 2. These data are consistent with a model in which loss of p53 function enables acquisition of stem cell properties, which are positively selected during tumor progression.
