MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells.
MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells.
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microRNA miR-34抑制人类胰腺癌肿瘤发射细胞。
DOI：
10.1371/journal.pone.0006816
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发表时间：
2009-08-28
期刊：
影响因子：
3.7
通讯作者：
Xu L
中科院分区：
文献类型：
--
作者：
Ji Q;Hao X;Zhang M;Tang W;Yang M;Li L;Xiang D;Desano JT;Bommer GT;Fan D;Fearon ER;Lawrence TS;Xu L
微小RNA（miRNA）通过其影响调节细胞增殖和/或细胞死亡的基因和蛋白质的表达的能力而与癌症的发生和发展有关。最近发现三种miRNA miR-34家族成员的转录直接受p53调控。受miR-34调控的靶蛋白包括Notch途径蛋白和Bcl-2，这表明miR-34在癌症干细胞的维持和存活中可能起作用。我们研究了miR-34在p53突变的人胰腺癌细胞系MiaPaCa 2和BxPC 3中的作用，以及与胰腺癌干细胞的潜在联系。通过转染miR-34模拟物或用慢病毒miR-34-MIF感染来恢复胰腺癌细胞中的miR-34表达下调Bcl-2和Notch 1/2。恢复miR-34可显著抑制克隆形成细胞的生长和侵袭，诱导细胞凋亡和G1和G2/M期阻滞，并使细胞对化疗和放疗敏感。我们鉴定了CD 44 +/CD 133 + MiaPaCa 2细胞富含肿瘤球形成和肿瘤起始细胞或具有高水平Notch/Bcl-2和miR-34缺失的癌症干/祖细胞。更重要的是，miR-34恢复导致肿瘤起始细胞群减少87%，同时显著抑制体外肿瘤球生长和体内肿瘤形成。我们的研究结果表明，miR-34可以恢复，至少部分，在p53缺陷的人胰腺癌细胞中的p53的肿瘤抑制功能。我们的数据支持miR-34可能参与胰腺癌干细胞自我更新的观点，可能通过直接调节下游靶点Bcl-2和Notch，这意味着miR-34可能在胰腺癌干细胞自我更新和/或细胞命运决定中发挥重要作用。miR-34的恢复可能作为p53-miR 34缺失的人胰腺癌的新型分子治疗具有重要的前景，可能通过抑制胰腺癌干细胞来实现。
MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34 family members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are Notch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer stem cells. We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines MiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the pancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-2 and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and G2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+ MiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumor-initiating cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo. Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function of the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in pancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch, implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination. Restoration of miR-34 may hold significant promise as a novel molecular therapy for human pancreatic cancer with loss of p53–miR34, potentially via inhibiting pancreatic cancer stem cells.
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DOI：
10.1186/bcr920
发表时间：
2004
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Dontu G;Jackson KW;McNicholas E;Kawamura MJ;Abdallah WM;Wicha MS
通讯作者：
Wicha MS
影响因子：
64.8
作者：
He, Lin;He, Xingyue;Hannon, Gregory J.
通讯作者：
Hannon, Gregory J.
影响因子：
11.2
作者：
Li, Chenwei;Heidt, David G.;Simeone, Diane M.
通讯作者：
Simeone, Diane M.
影响因子：
11.2
作者：
Corney, David C.;Flesken-Nikitin, Andrea;Nikitin, Alexander Yu.
通讯作者：
Nikitin, Alexander Yu.
影响因子：
23.9
作者：
Hermann, Patrick C.;Huber, Stephan L.;Heeschen, Christopher
通讯作者：
Heeschen, Christopher