Autophagy-active beclin-1 correlates with favourable clinical outcome in non-Hodgkin lymphomas.
The expression of beclin-1, an oncosuppressor monoallelically deleted in >60% epithelial cancers, has been shown to be developmentally regulated in T and B lymphocytes. By interacting with either bcl-2 or class III phosphatidyl-inositol-3-phosphate kinase, beclin-1 regulates apoptosis and autophagy, two processes crucial for lymphatic tissue homeostasis. We analyzed the potential link between beclin-1-mediated autophagy and the malignant behaviour of lymphomas. The tissue expression of beclin-1 was analyzed in a large series of non-Hodgkin lymphomas and correlated with patient's clinical outcome. By immunofluorescence, beclin-1 staining showed faintly detectable and diffusely distributed in the cytoplasm (regarded as negative) or confined to the perinuclear region as large and brilliant puncta suggestive of macro-aggregate reactivity (regarded as positive). The positive expression of beclin-1 well correlated with the presence of LC3-positive autophagic vacuoles and was inversely correlated with the expression of bcl-2. Non-Hodgkin lymphomas in which > or =20% of tumour cells expressed high level of beclin-1 aggregates were associated with a complete (57%) or partial (35%) remission. The 5-year overall survival probability, calculated by the Kaplan-Meier method, was 92% and 42% in beclin-1-expressing non-Hodgkin lymphomas with > or =20% and <20% positive cells, respectively (log-rank test, P<0.000.1). In Cox multivariate analysis, the level of beclin-1 expression, adjusted for patient's age and pathologic stage, revealed to be significantly correlated with patient's survival (P<0.0001). This is the first demonstration of the involvement of beclin-1 and autophagy in the clinical behaviour of non-Hodgkin lymphomas. The present data are compatible with the hypothesis that non-Hodgkin lymphomas with upregulated autophagy are more responsive to chemotherapy and indicate that beclin-1 could be a valuable independent prognostic factor in this heterogeneous group of tumours.
Nicotra
Giuseppina
G
Laboratorio di Patologia Molecolare del Dipartimento di Scienze Mediche, Novara, Italy.
Mercalli
Francesca
F
Peracchio
Claudia
C
Castino
Roberta
R
Follo
Carlo
C
Valente
Guido
G
Isidoro
Ciro
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D053208:Kaplan-Meier Estimate; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D014408:Biomarkers, Tumor; D008565:Membrane Proteins