Cationic polyurethanes-short branch PEI-mediated delivery of Mir145 inhibited epithelial–mesenchymal transdifferentiation and cancer stem-like properties and in lung adenocarcinoma

The high invasiveness and frequent recurrence of lung adenocarcinoma (LAC) are major reasons for treatment failures and poor prognoses. Alterations in microRNAs (miRNAs) expression have been shown in lung cancers. Recent reports have demonstrated that tumors contain a small subpopulation of cancer s...

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Veröffentlicht in:Journal of controlled release 2012-04, Vol.159 (2), p.240-250
Hauptverfasser: Chiou, Guang-Yuh, Cherng, Jong-Yuh, Hsu, Han-Shui, Wang, Mong-Lien, Tsai, Chun-Ming, Lu, Kai-Hsi, Chien, Yueh, Hung, Shih-Chieh, Chen, Yi-Wei, Wong, Chiang-Ing, Tseng, Ling-Ming, Huang, Pin-I, Yu, Cheng-Chia, Hsu, Wen-Huh, Chiou, Shih-Hwa
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container_end_page 250
container_issue 2
container_start_page 240
container_title Journal of controlled release
container_volume 159
creator Chiou, Guang-Yuh
Cherng, Jong-Yuh
Hsu, Han-Shui
Wang, Mong-Lien
Tsai, Chun-Ming
Lu, Kai-Hsi
Chien, Yueh
Hung, Shih-Chieh
Chen, Yi-Wei
Wong, Chiang-Ing
Tseng, Ling-Ming
Huang, Pin-I
Yu, Cheng-Chia
Hsu, Wen-Huh
Chiou, Shih-Hwa
description The high invasiveness and frequent recurrence of lung adenocarcinoma (LAC) are major reasons for treatment failures and poor prognoses. Alterations in microRNAs (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 Oct4highSox2highFascin1highmiR145low 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-bearing mice. 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. [Display omitted]
doi_str_mv 10.1016/j.jconrel.2012.01.014
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Alterations in microRNAs (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 Oct4highSox2highFascin1highmiR145low 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-bearing mice. 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. [Display omitted]</description><identifier>ISSN: 0168-3659</identifier><identifier>EISSN: 1873-4995</identifier><identifier>DOI: 10.1016/j.jconrel.2012.01.014</identifier><identifier>PMID: 22285547</identifier><identifier>CODEN: JCREEC</identifier><language>eng</language><publisher>Kidlington: Elsevier B.V</publisher><subject>adenocarcinoma ; Adenocarcinoma - drug therapy ; Adenocarcinoma - genetics ; Adenocarcinoma - pathology ; Adenocarcinoma of Lung ; Animals ; Biological and medical sciences ; Cations ; Cell Culture Techniques ; Cell Movement - drug effects ; Cell Movement - radiation effects ; Cell Survival - drug effects ; Cell Survival - genetics ; Cell Transdifferentiation ; Cells, Cultured ; correlation ; Drug Carriers - chemistry ; Epithelial-Mesenchymal Transition - drug effects ; Epithelial-Mesenchymal Transition - genetics ; Epithelial–mesenchymal transdifferentiation ; Fascin1 ; Gamma Rays ; Gene Transfer Techniques ; General pharmacology ; Humans ; in vivo studies ; Lung adenocarcinoma ; lung neoplasms ; Lung Neoplasms - drug therapy ; Lung Neoplasms - genetics ; Lung Neoplasms - pathology ; Medical sciences ; metastasis ; Mice ; Mice, Nude ; microRNA ; MicroRNAs - administration &amp; dosage ; MicroRNAs - genetics ; MicroRNAs - therapeutic use ; miR145 ; Neoplasm Invasiveness ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - pathology ; Oct4 ; patients ; Pharmaceutical technology. 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Alterations in microRNAs (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 Oct4highSox2highFascin1highmiR145low 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-bearing mice. 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. [Display omitted]</description><subject>adenocarcinoma</subject><subject>Adenocarcinoma - drug therapy</subject><subject>Adenocarcinoma - genetics</subject><subject>Adenocarcinoma - pathology</subject><subject>Adenocarcinoma of Lung</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cations</subject><subject>Cell Culture Techniques</subject><subject>Cell Movement - drug effects</subject><subject>Cell Movement - radiation effects</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - genetics</subject><subject>Cell Transdifferentiation</subject><subject>Cells, Cultured</subject><subject>correlation</subject><subject>Drug Carriers - chemistry</subject><subject>Epithelial-Mesenchymal Transition - drug effects</subject><subject>Epithelial-Mesenchymal Transition - genetics</subject><subject>Epithelial–mesenchymal transdifferentiation</subject><subject>Fascin1</subject><subject>Gamma Rays</subject><subject>Gene Transfer Techniques</subject><subject>General pharmacology</subject><subject>Humans</subject><subject>in vivo studies</subject><subject>Lung adenocarcinoma</subject><subject>lung neoplasms</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - pathology</subject><subject>Medical sciences</subject><subject>metastasis</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>microRNA</subject><subject>MicroRNAs - administration &amp; dosage</subject><subject>MicroRNAs - genetics</subject><subject>MicroRNAs - therapeutic use</subject><subject>miR145</subject><subject>Neoplasm Invasiveness</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Oct4</subject><subject>patients</subject><subject>Pharmaceutical technology. Pharmaceutical industry</subject><subject>Pharmacology. Drug treatments</subject><subject>phenotype</subject><subject>Polyethyleneimine - chemistry</subject><subject>Polyurethanes - chemistry</subject><subject>prognosis</subject><subject>relapse</subject><subject>reverse transcriptase polymerase chain reaction</subject><subject>sorting</subject><subject>Sox2</subject><subject>stem cells</subject><subject>Tumor Stem Cell Assay</subject><issn>0168-3659</issn><issn>1873-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcGO0zAQhiMEYsvCIwC-IHFJsR3baU4IVQustAgk2HPk2JOti2MX212pN96Bd-GBeBIm2wJHpJHmMN_MP_r_qnrK6JJRpl5tl1sTQwK_5JTxJWVY4l61YKu2qUXXyfvVArlV3SjZnVWPct5SSmUj2ofVGed8JaVoF9XPtS4uBmfILvrDPkHZ6AC5zpuYChmSDmZDPl1c1hNYpwtYYsG7W0gHEkfywSUmJHFh4wY3D2HnygYB7X99_zFBBlw_TNqTgpeydeMICUJxd6JEB0sMKkAiucBUe_cVyC7FHaTiIN_NXSB-H26IthCi0cm4ECf9uHowap_hyamfV9dvL76s39dXH99drt9c1UawrtSMN90g7SA5bQXYRls5Cj2oziqLPgnaSN5Z0HwYpemElaCsZSvFmhUdDNfNefXyeBe_-raHXPrJZQPeo0lxn3uMomkVU5IjKo-oSTHnBGO_S27S6YDQzKl-258i6-fIesqwBO49O0nsBzT579afjBB4cQJ0NtqPcyYu_-Nkx3gnZ-75kRt17PVNQub6MypJSlmrFJ9ffH0kAC27dZD6bBxGhNEmMKW30f3n2d__1cZk</recordid><startdate>20120430</startdate><enddate>20120430</enddate><creator>Chiou, Guang-Yuh</creator><creator>Cherng, Jong-Yuh</creator><creator>Hsu, Han-Shui</creator><creator>Wang, Mong-Lien</creator><creator>Tsai, Chun-Ming</creator><creator>Lu, Kai-Hsi</creator><creator>Chien, Yueh</creator><creator>Hung, Shih-Chieh</creator><creator>Chen, Yi-Wei</creator><creator>Wong, Chiang-Ing</creator><creator>Tseng, Ling-Ming</creator><creator>Huang, Pin-I</creator><creator>Yu, Cheng-Chia</creator><creator>Hsu, Wen-Huh</creator><creator>Chiou, Shih-Hwa</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>FBQ</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20120430</creationdate><title>Cationic polyurethanes-short branch PEI-mediated delivery of Mir145 inhibited epithelial–mesenchymal transdifferentiation and cancer stem-like properties and in lung adenocarcinoma</title><author>Chiou, Guang-Yuh ; Cherng, Jong-Yuh ; Hsu, Han-Shui ; Wang, Mong-Lien ; Tsai, Chun-Ming ; Lu, Kai-Hsi ; Chien, Yueh ; Hung, Shih-Chieh ; Chen, Yi-Wei ; Wong, Chiang-Ing ; Tseng, Ling-Ming ; Huang, Pin-I ; Yu, Cheng-Chia ; Hsu, Wen-Huh ; Chiou, Shih-Hwa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c419t-1239b5db52074ed3ad5f4ab69d6d873403529dea2bf5c94d5e6dd1861380bc2a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>adenocarcinoma</topic><topic>Adenocarcinoma - drug therapy</topic><topic>Adenocarcinoma - genetics</topic><topic>Adenocarcinoma - pathology</topic><topic>Adenocarcinoma of Lung</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cations</topic><topic>Cell Culture Techniques</topic><topic>Cell Movement - drug effects</topic><topic>Cell Movement - radiation effects</topic><topic>Cell Survival - drug effects</topic><topic>Cell Survival - genetics</topic><topic>Cell Transdifferentiation</topic><topic>Cells, Cultured</topic><topic>correlation</topic><topic>Drug Carriers - chemistry</topic><topic>Epithelial-Mesenchymal Transition - drug effects</topic><topic>Epithelial-Mesenchymal Transition - genetics</topic><topic>Epithelial–mesenchymal transdifferentiation</topic><topic>Fascin1</topic><topic>Gamma Rays</topic><topic>Gene Transfer Techniques</topic><topic>General pharmacology</topic><topic>Humans</topic><topic>in vivo studies</topic><topic>Lung adenocarcinoma</topic><topic>lung neoplasms</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - pathology</topic><topic>Medical sciences</topic><topic>metastasis</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>microRNA</topic><topic>MicroRNAs - administration &amp; dosage</topic><topic>MicroRNAs - genetics</topic><topic>MicroRNAs - therapeutic use</topic><topic>miR145</topic><topic>Neoplasm Invasiveness</topic><topic>Neoplastic Stem Cells - drug effects</topic><topic>Neoplastic Stem Cells - pathology</topic><topic>Oct4</topic><topic>patients</topic><topic>Pharmaceutical technology. 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Alterations in microRNAs (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 Oct4highSox2highFascin1highmiR145low 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-bearing mice. 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. [Display omitted]</abstract><cop>Kidlington</cop><pub>Elsevier B.V</pub><pmid>22285547</pmid><doi>10.1016/j.jconrel.2012.01.014</doi><tpages>11</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0168-3659
ispartof Journal of controlled release, 2012-04, Vol.159 (2), p.240-250
issn 0168-3659
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language eng
recordid cdi_proquest_miscellaneous_1013761652
source MEDLINE; Elsevier ScienceDirect Journals
subjects adenocarcinoma
Adenocarcinoma - drug therapy
Adenocarcinoma - genetics
Adenocarcinoma - pathology
Adenocarcinoma of Lung
Animals
Biological and medical sciences
Cations
Cell Culture Techniques
Cell Movement - drug effects
Cell Movement - radiation effects
Cell Survival - drug effects
Cell Survival - genetics
Cell Transdifferentiation
Cells, Cultured
correlation
Drug Carriers - chemistry
Epithelial-Mesenchymal Transition - drug effects
Epithelial-Mesenchymal Transition - genetics
Epithelial–mesenchymal transdifferentiation
Fascin1
Gamma Rays
Gene Transfer Techniques
General pharmacology
Humans
in vivo studies
Lung adenocarcinoma
lung neoplasms
Lung Neoplasms - drug therapy
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Medical sciences
metastasis
Mice
Mice, Nude
microRNA
MicroRNAs - administration & dosage
MicroRNAs - genetics
MicroRNAs - therapeutic use
miR145
Neoplasm Invasiveness
Neoplastic Stem Cells - drug effects
Neoplastic Stem Cells - pathology
Oct4
patients
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
phenotype
Polyethyleneimine - chemistry
Polyurethanes - chemistry
prognosis
relapse
reverse transcriptase polymerase chain reaction
sorting
Sox2
stem cells
Tumor Stem Cell Assay
title Cationic polyurethanes-short branch PEI-mediated delivery of Mir145 inhibited epithelial–mesenchymal transdifferentiation and cancer stem-like properties and in lung adenocarcinoma
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