title: Cationic polyurethanes-short branch PEI-mediated delivery of Mir145 inhibited epithelial-mesenchymal transdifferentiation and cancer stem-like properties and in lung adenocarcinoma.
abstract: 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 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-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.
authors.affiliation: Institute of Pharmacology, National Yang-Ming University, Taiwan.
authors.forename: Guang-Yuh
authors.initials: GY
authors.lastname: Chiou
authors.forename: Jong-Yuh
authors.initials: JY
authors.lastname: Cherng
authors.forename: Han-Shui
authors.initials: HS
authors.lastname: Hsu
authors.forename: Mong-Lien
authors.initials: ML
authors.lastname: Wang
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Tsai
authors.forename: Kai-Hsi
authors.initials: KH
authors.lastname: Lu
authors.forename: Yueh
authors.initials: Y
authors.lastname: Chien
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Hung
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Chen
authors.forename: Chiang-Ing
authors.initials: CI
authors.lastname: Wong
authors.forename: Ling-Ming
authors.initials: LM
authors.lastname: Tseng
authors.forename: Pin-I
authors.initials: PI
authors.lastname: Huang
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Yu
authors.forename: Wen-Huh
authors.initials: WH
authors.lastname: Hsu
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002412:Cations; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D004337:Drug Carriers / Q000737:chemistry*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D005720:Gamma Rays; D018014:Gene Transfer Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D011094:Polyethyleneimine / Q000737:chemistry*; D011140:Polyurethanes / Q000737:chemistry*; D014410:Tumor Stem Cell Assay
chemical_list: D002412:Cations; D004337:Drug Carriers; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D011140:Polyurethanes; D011094:Polyethyleneimine