Cationic polyurethanes-short branch PEI-mediated delivery of Mir145 inhibited epithelial-mesenchymal transdifferentiation and cancer stem-like properties and in lung adenocarcinoma
Cationic polyurethanes-short branch PEI-mediated delivery of Mir145 inhibited epithelial-mesenchymal transdifferentiation and cancer stem-like properties and in lung adenocarcinoma
复制标题
DOI：
10.1016/j.jconrel.2012.01.014
复制
发表时间：
2012-04-30
影响因子：
10.8
通讯作者：
Chiou, Shih-Hwa
中科院分区：
文献类型：
--
作者：
Chiou, Guang-Yuh;Cherng, Jong-Yuh;Chiou, Shih-Hwa
肺腺癌（LAC）的高侵袭性和高复发性是导致治疗失败和预后不良的主要原因。micrornas （miRNAs）表达的改变已经在肺癌中得到证实。最近的报道表明，肿瘤中含有一小部分具有自我更新能力的癌症干细胞（CSCs），它们负责肿瘤的恶性转移、复发和放化疗耐药。然而，基于mirna的治疗lac相关CSCs （LAC-CSCs）的方法仍然模糊不清。通过miRNA/ mrna微阵列和定量RT-PCR，我们发现在LAC患者标本中，miR145的表达与Oct4/Sox2/Fascin1水平呈负相关，Oct4（高）Sox2（高）Fascin1（高）miR145（低）表型预示预后不良。我们通过侧群体分选或CD133标记物鉴定富集了LAC-CSCs，发现LAC-CSCs具有低miR145和高Oct4/Sox2/Fascin1表达、csc样特性和放化疗抗性。为了明确miR145的作用，我们使用聚氨酯-短分支-聚乙烯亚胺（PU-PEI）作为载体将miR145输送到lac - csc中。通过直接靶向Oct4/Sox2/Fascin1， pu - pei介导的miR145递送降低了lc - cscs的样细胞特性，并改善了lc - cscs的放化疗耐药。重要的是，miR145对肿瘤转移的抑制作用是通过抑制上皮-间充质转分化（EMT）和转移能力来介导的，部分通过调节Oct4/Sox2/Fascin1、Tcf4和Wnt5a来实现。最后，体内研究表明，pu - pei介导的miR145递送到异种移植肿瘤可减少肿瘤生长和转移，使肿瘤对放化疗敏感，并延长荷瘤小鼠的生存时间。我们的研究结果表明，miR145作为调节肺csc样细胞和EMT特性的开关，并为基于miR145的恶性肺癌治疗的临床前景提供了见解。爱思唯尔B.V.版权所有
The high invasiveness and frequent recurrence of lung adenocarcinoma (LAC) are major reasons for treatment failures and poor prognoses. Alterations inmicroRNAs (miRNAs) expression have been shown in lung cancers. Recent reports have demonstrated that tumors contain a small subpopulation of cancer stem cells (CSCs) that possesses self-renewing capacity and is responsible for tumor malignancy including metastasis, relapse, and chemoradioresistance. However, a miRNAs-based therapeutic approach in LAC-associated CSCs (LAC-CSCs) is still blurred. Using miRNA/mRNA-microarray and Quantitative RT-PCR, we found that the expression of miR145 is negatively correlated with the levels of Oct4/Sox2/Fascin1 in LAC patient specimens, and an Oct4(high)Sox2(high)Fascin1(high)miR145(low) phenotype predicted poor prognosis. We enriched LAC-CSCs by side population sorting or identification of CD133 markers and found that LAC-CSCs exhibited low miR145 and high Oct4/Sox2/Fascin1 expression, CSC-like properties, and chemoradioresistance. To clarify the role of miR145, we used a polyurethane-short branch-polyethylenimine (PU-PEI) as the vehicle to deliver miR145 into LAC-CSCs. PU-PEI-mediated miR145 delivery reduced CSC-like properties, and improved chemoradioresistance in LAC-CSCs by directly targeting Oct4/Sox2/Fascin1. Importantly, the repressive effect of miR145 on tumor metastasis was mediated by inhibiting the epithelial-mesenchymal transdifferentiation (EMT) and metastastic ability, partially by regulating Oct4/Sox2/Fascin1, Tcf4, and Wnt5a. Finally, in vivo study showed that PU-PEI-mediated miR145 delivery to xenograft tumors reduced tumor growth and metastasis, sensitized tumors to chemoradiotherapies, and prolonged the survival times of tumor-bearingmice. Our results demonstrated that miR145 acts as a switch regulating lung CSC-like and EMT properties, and provide insights into the clinical prospect of miR145-based therapies for malignant lung cancers. Crown Copyright (C) 2012 Published by Elsevier B.V. All rights reserved.