title: LincRNA-p21 Impacts Prognosis in Resected Non-Small Cell Lung Cancer Patients through Angiogenesis Regulation.
abstract: Long intergenic noncoding RNA-p21 (lincRNA-p21) is a long noncoding RNA transcriptionally activated by tumor protein p53 (TP53) and hypoxia inducible factor 1 alpha subunit (HIF1A). It is involved in the regulation of TP53-dependent apoptosis and the Warburg effect. We have investigated the role of lincRNA-p21 in NSCLC.
  
  
  
  LincRNA-p21 expression was assessed in tumor and normal tissue from 128 patients with NSCLC and correlated with time to relapse and cancer-specific survival (CSS). H23, H1299, and HCC-44 cell lines were cultured in hypoxic conditions after silencing of lincRNA-p21. The TaqMan human angiogenesis array was used to explore angiogenesis-related gene expression. Levels of the protein vascular endothelial growth factor A were measured by enzyme-linked immunosorbent assay in the cell supernatants. Angiogenic capability was measured by human umbilical vein endothelial cell tube formation assay. Microvascular density in tumor samples was analyzed by immunohistochemistry.
  
  
  
  LincRNA-p21 was down-regulated in tumor tissue, but no association was observed with TP53 mutational status. High lincRNA-p21 levels were associated with poor CSS in all patients (p = 0.032). When patients were classified according to histological subtypes, the impact of lincRNA-p21 was confined to patients with adenocarcinoma in both time to relapse (p = 0.006) and CSS (p < 0.001). To explain the poor outcome of patients with high lincRNA-p21 expression, we studied the role of lincRNA-p21 in angiogenesis in vitro and observed a global downregulation in the expression of angiogenesis-related genes when lincRNA-p21 was inhibited. Moreover, supernatants from lincRNA-p21-inhibited cells were significantly less angiogenic and had lower levels of secreted vascular endothelial growth factor A than controls did. Finally, tumor samples with high lincRNA-p21 levels had higher microvascular density.
  
  
  
  Our findings suggest that lincRNA-p21 affects outcome in patients with NSCLC adenocarcinoma through the regulation of angiogenesis.
authors: Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
authors: Joan J
authors: JJ
authors: Castellano
authors: Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain. Electronic address: anavarroponz@ub.edu.
authors: Alfons
authors: A
authors: Navarro
authors: Department of Medical Oncology, Clinic Institute of Haematological and Oncological Diseases, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS (August Pi i Sunyer Biomedical Research Institute), Barcelona, Spain.
authors: Nuria
authors: N
authors: Viñolas
authors: Department of Pneumology, Thorax Clínic Institute, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS (August Pi i Sunyer Biomedical Research Institute), CIBER of Respiratory Diseases (CIBERES), Barcelona, Spain.
authors: Ramon M
authors: RM
authors: Marrades
authors: Department of Pneumology, Thorax Clínic Institute, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS (August Pi i Sunyer Biomedical Research Institute), CIBER of Respiratory Diseases (CIBERES), Barcelona, Spain.
authors: Jorge
authors: J
authors: Moises
authors: Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
authors: Anna
authors: A
authors: Cordeiro
authors: Department of Pathology, The Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS (August Pi i Sunyer Biomedical Research Institute), CIBERES, Barcelona, Spain.
authors: Adela
authors: A
authors: Saco
authors: Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
authors: Carmen
authors: C
authors: Muñoz
authors: Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
authors: Dolors
authors: D
authors: Fuster
authors: Department of Thoracic Surgery, Thorax Clínic Institute, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain.
authors: Laureano
authors: L
authors: Molins
authors: Department of Pathology, The Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS (August Pi i Sunyer Biomedical Research Institute), CIBERES, Barcelona, Spain.
authors: Josep
authors: J
authors: Ramirez
authors: Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
authors: Mariano
authors: M
authors: Monzo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D062085:RNA, Long Noncoding; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Angiogenesis; Hypoxia; LincRNA-p21; Long noncoding RNAs; NSCLC