DICER1, DROSHA and miRNAs in patients with non-small cell lung cancer: implications for outcomes and histologic classification.
The clinical and functional significance of RNA-interference machinery in lung cancer is poorly understood. Besides, microRNAs (miRNA) have the potential to serve both as biomarkers and therapeutic agents, by personalizing diagnosis and therapy. In this study, we investigated whether the expression levels of DICER1 and DROSHA, components of the RNA-interference machinery, can predict survival, and whether the miRNA expression profiles can differentiate histologic subtypes in non-small cell lung cancer (NSCLC). Levels of DICER1, DROSHA and five different miRNAs were measured in NSCLC specimens (N = 115) by qRT-PCR assay and correlated with clinical outcomes. Low expression of DROSHA was associated with an increased median survival (154.2 versus 39.8 months, P = 0.016). Also, high DROSHA expression was associated with decreased median survival in the following subgroups: adenocarcinoma (P = 0.011), grade III tumors (P = 0.038) and low-stage patients (P = 0.014). In multivariate analyses, we found two independent predictors of reduced disease-specific survival: high DROSHA expression [hazards ratio = 2.24; P = 0.04] and advanced tumor stage (hazards ratio = 1.29, P = 0.02). In general, the overall tumor miRNA expression was downregulated in our cohort compared with normal tissues. Expression levels of hsa-let-7a (P = 0.005) and miR-16 (P = 0.003) miRNA were significantly higher in squamous cell carcinoma than in adenocarcinoma samples. This study supports the value of the expression profiling of the components of the miRNA-processing machinery in the prognosis of NSCLC patients, especially DROSHA expression levels. In addition, differential expression of miRNAs, such as hsa-let-7a and miR-16 may be helpful tools in the histologic subclassification of NSCLC.
Oncology Department, Hospital Universitario 12 de Octubre, Madrid, 28041, Spain.
C Vanesa
CV
Díaz-García
Alba
A
Agudo-López
Carlos
C
Pérez
José A
JA
López-Martín
J Luis
JL
Rodríguez-Peralto
Javier
J
de Castro
Ana
A
Cortijo
Miriam
M
Martínez-Villanueva
Lara
L
Iglesias
Rocío
R
García-Carbonero
Juan A
JA
Fresno Vara
Angelo
A
Gámez-Pozo
José
J
Palacios
Hernán
H
Cortés-Funes
Luis
L
Paz-Ares
M Teresa
MT
Agulló-Ortuño
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D011379:Prognosis; D043244:Ribonuclease III / Q000096:biosynthesis* / Q000235:genetics
D035683:MicroRNAs; C408087:DICER1 protein, human; C517918:DROSHA protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases