Upregulation of PTEN in glioma cells by cord blood mesenchymal stem cells inhibits migration via downregulation of the PI3K/Akt pathway.
Upregulation of PTEN in glioma cells by cord blood mesenchymal stem cells inhibits migration via downregulation of the PI3K/Akt pathway.
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DOI：
10.1371/journal.pone.0010350
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发表时间：
2010-04-26
期刊：
影响因子：
3.7
通讯作者：
Rao JS
中科院分区：
文献类型：
--
作者：
Dasari VR;Kaur K;Velpula KK;Gujrati M;Fassett D;Klopfenstein JD;Dinh DH;Rao JS
PTEN(第10号染色体上缺失的磷酸酶和张力蛋白同源基因)是一种肿瘤抑制基因，与多种人类癌症有关，包括胶质母细胞瘤。PTEN是PI3K/Akt信号通路的主要负调控因子。大多数人类胶质瘤表现出高水平的激活Akt，而这些肿瘤中只有不到一半携带PTEN突变或纯合子缺失。间充质干细胞追踪肿瘤细胞的独特能力使其成为潜在的治疗剂。基于这种能力，已开发出使用间充质干细胞治疗胶质母细胞瘤的新方法。然而，胶质瘤细胞与干细胞相互作用的分子机制尚不清楚。为了研究PTEN基因上调抑制胶质瘤细胞迁移的机制，我们研究了两个胶质瘤细胞系(SNB19和U251)和两个胶质瘤异种移植细胞系(4910和5310)单独以及与人脐血间充质干细胞(HUCBSC)共同培养的情况。免疫荧光和免疫印迹分析显示，共培养的胶质瘤细胞PTEN表达增加。基因芯片分析显示，PTEN基因的上调与Akt、Jun、MAPK14、PDK2、PI3K、PTK2、RAS和RAF1等基因的下调有关。PTEN和Akt基因的逆转录-聚合酶链式反应分析证实了这一结果。在体外条件下，PTEN的上调导致胶质瘤细胞迁移能力的抑制。此外，与人脐血干细胞共培养时，胶质瘤细胞的创面愈合能力明显受到抑制。在体内条件下，hUCBSC对裸鼠颅内肿瘤生长有抑制作用。此外，hUCBSC上调PTEN并降低XIAP和Akt的水平，这是抑制小鼠脑内肿瘤生长的主要原因。我们的研究表明，hUCBSC上调了胶质瘤细胞和裸鼠肿瘤中PTEN的表达，下调了Akt和PI3K信号通路分子。这导致了胶质瘤细胞的迁移和伤口愈合特性的抑制。综上所述，我们的结果提示hUCBSC是一种治疗恶性胶质瘤的药物。
PTEN (phosphatase and tensin homologue deleted on chromosome ten) is a tumor suppressor gene implicated in a wide variety of human cancers, including glioblastoma. PTEN is a major negative regulator of the PI3K/Akt signaling pathway. Most human gliomas show high levels of activated Akt, whereas less than half of these tumors carry PTEN mutations or homozygous deletions. The unique ability of mesenchymal stem cells to track down tumor cells makes them as potential therapeutic agents. Based on this capability, new therapeutic approaches have been developed using mesenchymal stem cells to cure glioblastoma. However, molecular mechanisms of interactions between glioma cells and stem cells are still unknown. In order to study the mechanisms by which migration of glioma cells can be inhibited by the upregulation of the PTEN gene, we studied two glioma cell lines (SNB19 and U251) and two glioma xenograft cell lines (4910 and 5310) alone and in co-culture with human umbilical cord blood-derived mesenchymal stem cells (hUCBSC). Co-cultures of glioma cells showed increased expression of PTEN as evaluated by immunofluorescence and immunoblotting assays. Upregulation of PTEN gene is correlated with the downregulation of many genes including Akt, JUN, MAPK14, PDK2, PI3K, PTK2, RAS and RAF1 as revealed by cDNA microarray analysis. These results have been confirmed by reverse-transcription based PCR analysis of PTEN and Akt genes. Upregulation of PTEN resulted in the inhibition of migration capability of glioma cells under in vitro conditions. Also, wound healing capability of glioma cells was significantly inhibited in co-culture with hUCBSC. Under in vivo conditions, intracranial tumor growth was inhibited by hUCBSC in nude mice. Further, hUCBSC upregulated PTEN and decreased the levels of XIAP and Akt, which are responsible for the inhibition of tumor growth in the mouse brain. Our studies indicated that upregulation of PTEN by hUCBSC in glioma cells and in the nude mice tumors downregulated Akt and PI3K signaling pathway molecules. This resulted in the inhibition of migration as well as wound healing property of the glioma cells. Taken together, our results suggest hUCBSC as a therapeutic agent in treating malignant gliomas.
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影响因子：
45.3
作者：
Chakravarti, A;Zhai, G;Loeffler, JS
通讯作者：
Loeffler, JS
影响因子：
5.7
作者：
Gallia GL;Tyler BM;Hann CL;Siu IM;Giranda VL;Vescovi AL;Brem H;Riggins GJ
通讯作者：
Riggins GJ
影响因子：
3.8
作者：
Larkins TL;Nowell M;Singh S;Sanford GL
通讯作者：
Sanford GL
影响因子：
5.2
作者：
Bieback, K;Kern, S;Eichler, H
通讯作者：
Eichler, H
影响因子：
9.2
作者：
Leslie, Nick R.;Yang, Xuesong;Downes, C. Peter;Weijer, Cornelis J.
通讯作者：
Weijer, Cornelis J.