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. [Cancer Res 2009;69(13):5553-9]

Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer

“…As loss of miR-15 and miR-16 has been described as a key event in cancer progression in different tumor types (Cimmino et al, 2005;Bandi et al, 2009;Bhattacharya et al, 2009;Roccaro et al, 2009;Klein et al, 2010), our data suggest that the tumor suppressor activity of miR-15 and miR-16 is not confined to the cancer cell compartment, but is shared by the tumor microenvironment. MicroRNAs control the expression of multiple targets, offering a great advantage as a possible multiblocking therapeutic approach.…”

An integrated transcriptional regulatory circuit that reinforces the breast cancer stem cell state

“…In accord with the defining high tumor formation properties of CSCs, all of these miRNAs have been have generally been described as tumor suppressors (e.g., see refs. [26][27][28][29][30][31].…”

Genetic and epigenetic changes in lung carcinoma and their clinical implications

“…137 Such miRNAs as miR-126, miR-31, miR-519c, Let-7a, miR-133B, miR-15a, miR-16, and miR-183 have been found to regulate lung cancer cell proliferation, migration and invasion by targeting specific molecules, including Crk, EGFL7, VEGF, LATS2, PPP2R2A, HIF-1a, NIRF, MCL-1, BCL2L2, cyclins D1, D2 and E1, and Ezrin. [138][139][140][141][142][143][144][145][146] Abnormally expressed miRNAs may have potential as markers in lung cancer diagnosis, treatment response, and prognosis. Has-miR-205, which suppresses epithelial-to-mesenchymal transition, has been identified as a highly specific marker for squamous carcinoma of the lung.…”