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

Bandi, Nora; Zbinden, Samuel; Gugger, Mathias; Arnold, Marlene; Kocher, Verena; Hasan, Lara; Kappeler, Andreas; Brunner, Thomas; Vassella, Erik (2009). 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. Cancer research, 69(13), pp. 5553-9. Birmingham, Ala.: American Association for Cancer Research AACR 10.1158/0008-5472.CAN-08-4277

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology
04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Zbinden, Stephan; Gugger, Mathias; Arnold, Marlene; Kocher, Verena; Kappeler, Andreas; Brunner, Thomas and Vassella, Erik

ISSN:

0008-5472

ISBN:

19549910

Publisher:

American Association for Cancer Research AACR

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:08

Last Modified:

10 Nov 2014 07:27

Publisher DOI:

10.1158/0008-5472.CAN-08-4277

PubMed ID:

19549910

Web of Science ID:

000267691800037

URI:

https://boris.unibe.ch/id/eprint/29969 (FactScience: 165541)

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