miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer.

Abstract

MicroRNAs (miRNA) are negative regulators of gene expression at the posttranscriptional level, which are involved in tumorigenesis. Two miRNAs, miR-15a and miR-16, which are located at chromosome 13q14, have been implicated in cell cycle control and apoptosis, but little information is available about their role in solid tumors. To address this question, we established a protocol to quantify miRNAs from laser capture microdissected tissues. Here, we show that miR-15a/miR-16 are frequently deleted or down-regulated in squamous cell carcinomas and adenocarcinomas of the lung. In these tumors, expression of miR-15a/miR-16 inversely correlates with the expression of cyclin D1. In non-small cell lung cancer (NSCLC) cell lines, cyclins D1, D2, and E1 are directly regulated by physiologic concentrations of miR-15a/miR-16. Consistent with these results, overexpression of these miRNAs induces cell cycle arrest in G(1)-G(0). Interestingly, H2009 cells lacking Rb are resistant to miR-15a/miR-16-induced cell cycle arrest, whereas reintroduction of functional Rb resensitizes these cells to miRNA activity. In contrast, down-regulation of Rb in A549 cells by RNA interference confers resistance to these miRNAs. Thus, cell cycle arrest induced by these miRNAs depends on the expression of Rb, confirming that G(1) cyclins are major targets of miR-15a/miR-16 in NSCLC. Our results indicate that miR-15a/miR-16 are implicated in cell cycle control and likely contribute to the tumorigenesis of NSCLC.

• Authors: Nora Bandi, Samuel Zbinden, Mathias Gugger, Marlene Arnold, Verena Kocher, Lara Hasan, Andreas Kappeler, Thomas Brunner, Erik Vassella
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 13 Pg. 5553-9 (Jul 01 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19549910 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MIRN15 microRNA, human
• MIRN16 microRNA, human
• MicroRNAs
• RNA, Neoplasm
• Retinoblastoma Protein

Topics

• Apoptosis (genetics)
• Carcinoma, Non-Small-Cell Lung (genetics, pathology)
• Cell Cycle (genetics, physiology)
• Chromosome Mapping
• Chromosomes, Human, Pair 13
• Gene Deletion
• Gene Expression Regulation
• Humans
• Lung Neoplasms (genetics, pathology)
• MicroRNAs (genetics)
• RNA, Neoplasm (genetics)
• Retinoblastoma Protein (physiology)