miRNA-130a Targets ATG2B and DICER1 to Inhibit Autophagy and Trigger Killing of Chronic Lymphocytic Leukemia Cells

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 7; pp. 1763 - 1772
• Main Authors: Kovaleva, Valentina, Mora, Rodrigo, Park, Yoon Jung, Plass, Christoph, Chiramel, Abhilash I., Bartenschlager, Ralf, Döhner, Hartmut, Stilgenbauer, Stephan, Pscherer, Armin, Lichter, Peter, Seiffert, Martina
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.04.2012
• Subjects: Antineoplastic agents; Autophagy; Autophagy-Related Proteins; Biological and medical sciences; Cancer; Carrier Proteins - genetics; Cell Line, Tumor; Cell Survival; DEAD-box RNA Helicases - genetics; Gene Expression Regulation, Leukemic; Hematologic and hematopoietic diseases; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; MicroRNAs - physiology; Pharmacology. Drug treatments; Ribonuclease III - genetics; Tumors; Vesicular Transport Proteins; RNA interference; Targeting; Micro RNA; Malignant hemopathy; Autophagy; In vitro; Gene silencing; Target; Chronic lymphocytic leukemia; Lymphoproliferative syndrome; Inhibitor; Cell; Cancer
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-11-3671

Toxicity and relapses from the immunochemotherapy used to treat chronic lymphocytic leukemia (CLL) prompt continued interest in gentle but effective targeted treatment options for the mainly elderly population suffering from this disease. Here, we report the definition of critical CLL cell survival pathways that can be targeted by ectopic reexpression of the miRNA genes miR-130a and miR-143 which are widely downregulated in CLL. Notably, miR-130a inhibited autophagy by reducing autophagosome formation, an effect mediated by downregulation of the genes ATG2B and DICER1, the latter of which is a major component of the miRNA silencing machinery. In support of the concept of a fundamental connection between miRNA disregulation and altered autophagic flux in this cancer, we showed that RNA interference–mediated knockdown of DICER1 expression was sufficient to reduce autophagy in primary or established cultures of CLL cells. Together, our findings show that miR-130a modulates cell survival programs by regulating autophagic flux, and they define roles for miR-130a and Dicer1 in a regulatory feedback loop that mediates CLL cell survival. Cancer Res; 72(7); 1763–72. ©2012 AACR.