The significance of PIWI family expression in human lung embryogenesis and non-small cell lung cancer.
The expression of Piwi-interacting RNAs, small RNAs that bind to PIWI proteins, was until recently believed to be limited to germinal stem cells. We have studied the expression of PIWI genes during human lung embryogenesis and in paired tumor and normal tissue prospectively collected from 71 resected non-small-cell lung cancer patients. The mRNA expression analysis showed that PIWIL1 was highly expressed in 7-week embryos and downregulated during the subsequent weeks of development. PIWIL1 was expressed in 11 of the tumor samples but in none of the normal tissue samples. These results were validated by immunohistochemistry, showing faint cytoplasmic reactivity in the PIWIL1-positive samples. Interestingly, the patients expressing PIWIL1 had a shorter time to relapse (TTR) (p = 0.006) and overall survival (OS) (p = 0.0076) than those without PIWIL1 expression. PIWIL2 and 4 were downregulated in tumor tissue in comparison to the normal tissue (p < 0.001) and the patients with lower levels of PIWIL4 had shorter TTR (p = 0.048) and OS (p = 0.033). In the multivariate analysis, PIWIL1 expression emerged as an independent prognostic marker. Using 5-Aza-dC treatment and bisulfite sequencing, we observed that PIWIL1 expression could be regulated in part by methylation. Finally, an in silico study identified a stem-cell expression signature associated with PIWIL1 expression.
Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
Alfons
A
Navarro
Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
Rut
R
Tejero
Department of Medical Oncology, Institut Clinic Malalties Hemato-Oncològiques (ICMHO), Hospital Clinic de Barcelona, University of Barcelona, IDIBAPS, Barcelona, Spain.
Nuria
N
Viñolas
Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
Anna
A
Cordeiro
Department of Pneumology, Institut Clínic del Tórax (ICT), Hospital Clinic de Barcelona, University of Barcelona, IDIBAPS, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain.
Ramon M
RM
Marrades
Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
Dolors
D
Fuster
Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
Oriol
O
Caritg
Department of Pneumology, Institut Clínic del Tórax (ICT), Hospital Clinic de Barcelona, University of Barcelona, IDIBAPS, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain.
Jorge
J
Moises
Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
Carmen
C
Muñoz
Department of Thoracic Surgery, Institut Clínic del Tórax (ICT), Hospital Clinic de Barcelona, University of Barcelona, Barcelona, Spain.
Laureano
L
Molins
Department of Pathology, Centro de Diagnóstico Biomédico (CDB), Hospital Clinic de Barcelona, University of Barcelona, IDIBAPS, CIBERES, Barcelona, Spain.
Josep
J
Ramirez
Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
Mariano
M
Monzo
D000368:Aged; D000369:Aged, 80 and over; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D045744:Cell Line, Tumor; D019175:DNA Methylation; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000196:embryology / Q000378:metabolism* / Q000601:surgery; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D016016:Proportional Hazards Models; D016601:RNA-Binding Proteins; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
D060565:Argonaute Proteins; D014408:Biomarkers, Tumor; C421088:PIWIL1 protein, human; C486868:PIWIL2 protein, human; C556795:PIWIL4 protein, human; D016601:RNA-Binding Proteins
NSCLC; PIWI proteins; PIWIL1; PIWIL4; piwiRNAs