來自澳大利亞紐卡斯爾大學和安徽醫(yī)科大學等機構的研究人員,,在新研究中證實5-磷酸酶PIB5PA通過調(diào)控PI3K/Akt信號在黑色素瘤中發(fā)揮了重要的腫瘤抑制作用。研究論文發(fā)表在2月26日的《自然通訊》(Nature Communications)雜志上,。
領導這一研究的是華人科學家張旭東(Xu Dong Zhang)教授?,F(xiàn)任澳大利亞卡瓦特瑪特紐卡斯爾醫(yī)院高級醫(yī)院科學家、腫瘤免疫室負責人和澳大利亞紐卡斯爾大學醫(yī)學和公共衛(wèi)生學院教授,長期致力于黑色素瘤化療抵抗及相關機制的研究工作,,在腫瘤化療抵抗及相關機制研究方面具有很深的學術造詣,。
黑色素瘤是由異常黑素細胞過度增生引發(fā)的常見的皮膚腫瘤,惡性程度極高,,占皮膚腫瘤死亡病例的極大部分,。多發(fā)生于皮膚或接近皮膚的黏膜,也見于軟腦膜和脈絡膜,。其發(fā)病率隨人種,、地域、種族的不同而存有所差異,,白種人的發(fā)病率遠較黑種人高,,居住在澳大利亞昆士蘭州的白種人其發(fā)病率高達17/10萬。我國雖屬黑色素瘤的低發(fā)區(qū),,但近年來發(fā)病率也呈不斷上升趨勢,。
磷脂酰肌醇3-激酶(PI3K)家族參與多種信號通路,調(diào)節(jié)細胞的主要功能,。正常情況下,,有其活化而產(chǎn)生的類脂產(chǎn)物3,4-二磷酸磷脂酰肌醇〔PI(3,4)P2〕和3,4,5-三磷酸磷脂酰肌醇〔PI(3,4,5)P3〕作為第二信使結合并激活多種細胞內(nèi)靶蛋白,,形成一個信號級聯(lián)復合物,最終調(diào)節(jié)細胞的增殖,、分化,、存活和遷移等。在PI3K家族中,,IA型PI3K和其下游分子絲氨酸/蘇氨酸蛋白激酶Akt(或PKB)所組成的信號通路,,因其與腫瘤發(fā)生發(fā)展的相關性而備受矚目。近年來的研究發(fā)現(xiàn)在多達70%的黑色素瘤中均有PI3K/Akt信號的組成性激活,。
在這篇文章中,,研究人員證實黑色素瘤中磷脂酰肌醇4,5-二磷酸5磷酸酶A (PIB5PA)的表達下降與PI3K/Akt信號激活相關,PIB5PA在黑色素瘤中具有重要腫瘤抑制作用,。在體外實驗中,,研究人員證實過表達PIB5PA可以阻斷Akt激活,抑制黑色素瘤細胞增殖,,破壞細胞存活,。在體外實驗中,他們?nèi)〉昧艘恢碌慕Y果,,證實PIB5PA可減緩異種移植物模型中的黑色素瘤生長,。與之相反,當研究人員抑制PIB5PA時,,證實促進了黑色素細胞增殖及非貼附性生長,。
在進一步的機制研究中,研究人員發(fā)現(xiàn)DNA拷貝數(shù)喪失是一部分黑色素瘤中PIB5PA下調(diào)的重要原因,。此外,,組蛋白去乙酰化酶HDAC2和HDAC3通過結合PIB5PA基因啟動子轉錄因子Sp1,,介導的組蛋白低乙?;╤istone hypoacetylation)也是黑色素瘤中抑制PIB5PA的一種常見機制。
這些研究結果證實了PIB5PA的腫瘤抑制作用,,并揭示了其在黑色素瘤中的相關調(diào)控機制,。從而為改善黑色素瘤治療提供了有潛力的治療靶點和研究新方向。(生物谷Bioon.com)
doi:10.1038/ncomms2489
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PI(4,5)P2 5-phosphatase A regulates PI3K/Akt signalling and has a tumour suppressive role in human melanoma
Yan Ye, Lei Jin, James S-Wilmott, Wang Lai Hu, Benafsha Yosufi, Rick F-Thorne, Tao Liu, Helen Rizos, Xu Guang Yan, Li Dong, Kwang Hong Tay, Hsin-Yi Tseng, Su Tang Guo, Charles E-de Bock, Chen Chen Jiang, Chun Yan Wang, Mian Wu, Lin Jie Zhang, Peter Hersey, Richard A- Scolyer, Xu Dong Zhang.
Inositol polyphosphate 5-phosphatases can terminate downstream signalling of phosphatidylinositol-3 kinase; however, their biological role in the pathogenesis of cancer is controversial. Here we report that the inositol polyphosphate 5-phosphatase, phosphatidylinositol 4,5-bisphosphate 5-phosphatase, has a tumour suppressive role in melanoma. Although it is commonly downregulated in melanoma, overexpression of phosphatidylinositol 4,5-bisphosphate 5-phosphatase blocks Akt activation, inhibits proliferation and undermines survival of melanoma cells in vitro, and retards melanoma growth in a xenograft model. In contrast, knockdown of phosphatidylinositol 4,5-bisphosphate 5-phosphatase results in increased proliferation and anchorage-independent growth of melanocytes. Although DNA copy number loss is responsible for downregulation of phosphatidylinositol 4,5-bisphosphate 5-phosphatase in a proportion of melanomas, histone hypoacetylation mediated by histone deacetylases HDAC2 and HDAC3 through binding to the transcription factor Sp1 at the PIB5PA gene promoter appears to be another commonly involved mechanism. Collectively, these results establish the tumour suppressive role of phosphatidylinositol 4,5-bisphosphate 5-phosphatase and reveal mechanisms involved in its downregulation in melanoma.