title: MicroRNA-183 promotes migration and invasion of CD133(+)/CD326(+) lung adenocarcinoma initiating cells via PTPN4 inhibition.
abstract: Non-small cell lung cancer (NSCLC) is the most common cancer worldwide and is a leading cause of lung cancer mortality due to early stage metastases. Cancer stem-like cells (CSLCs) or tumor-initiating cells (TICs) are rare subpopulation cells that are responsible for maintaining tumor growth and invasion leading to recurrence and metastasis. Previous studies revealed that miR-183 can mediate the invasiveness and growth of NSCLC. However, the exact role of miR-183 in regulating the biological behavior of CSLCs in NSCLC remains unclear. In the present study, we explored the regulation of protein tyrosine phosphatase non-receptor type 4 (PTPN4) by miR-183 in vitro using luciferase reporter assays, and we further analyzed the effects of miR-183 on the invasiveness of CSLCs in vitro and in vivo using transwell and bioluminescence assays. Following our finding that miR-183 binds to PTPN4 messenger RNA (mRNA) to prevent its translation through the 3'-untranslated region (UTR), we found that overexpression of miR-183 in CSLCs decreased PTPN4 protein levels while inhibition of miR-183 increased PTPN4 protein levels. The suppression of PTPN4 levels in CSLCs by miR-183 paralleled with a significant promotion in their motility in vitro and in vivo, while anti-sense miR-183 increased PTPN4 levels in CSLCs, which paralleled with a significant decrease in their invasiveness. Furthermore, correlation analysis between miR-183 and PTPN4 in clinical samples demonstrated a statistically significant inverse correlation between PTPN4 mRNA levels and miR-183. In brief, our data indicate that miR-183 plays a pro-invasive role by inverse regulation of PTPN4, and this axis may be a new therapeutic target for suppressing the metastatic capability of CSLCs in NSCLC.
authors.affiliation: Institute of Cancer, Xiqiao Hospital, Third Military Medical University, Chongqing, 40037, China.
authors.forename: Conghui
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.|Ultrasonography, Xiqiao Hospital, Third Military Medical University, Chongqing, 40037, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
authors.forename: Hongru
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
authors.forename: Shaozhi
authors.initials: S
authors.lastname: Fu
authors.affiliation: Nuclear Medicine Department, The First Affiliated Hospital of Sichuan Medical University, Luzhou, Sichuan, 646000, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
authors.forename: Yunwei
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
authors.forename: Yuanmei
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Institute of Cancer, Xiqiao Hospital, Third Military Medical University, Chongqing, 40037, China. zhengtangchen@126.com.
authors.forename: Zhengtang
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China. lslinsheng@163.com.
authors.forename: Sheng
authors.initials: S
authors.lastname: Lin
mesh_terms: D000071916:AC133 Antigen; D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement; D000071858:Epithelial Cell Adhesion Molecule; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000473:pathology; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4 / Q000096:biosynthesis*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000071916:AC133 Antigen; D000071858:Epithelial Cell Adhesion Molecule; C533449:MIRN183 microRNA, human; D035683:MicroRNAs; C000606023:PROM1 protein, human; C516658:PTPN4 protein, human; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4
keywords: CD133/CD326; Cancer stem-like cells; PTPN4; Tumor-initiating cells; miR-183