MicroRNAs (miRNAs) are small, noncoding RNAs that regulate expression of many 
genes. Recent studies suggest roles of miRNAs in carcinogenesis. We and others 
have shown that expression profiles of miRNAs are different in lung cancer vs. 
normal lung, although the significance of this aberrant expression is poorly 
understood. Among the reported down-regulated miRNAs in lung cancer, the miRNA 
(miR)-29 family (29a, 29b, and 29c) has intriguing complementarities to the 
3'-UTRs of DNA methyltransferase (DNMT)3A and -3B (de novo methyltransferases), 
two key enzymes involved in DNA methylation, that are frequently up-regulated in 
lung cancer and associated with poor prognosis. We investigated whether miR-29s 
could target DNMT3A and -B and whether restoration of miR-29s could normalize 
aberrant patterns of methylation in non-small-cell lung cancer. Here we show 
that expression of miR-29s is inversely correlated to DNMT3A and -3B in lung 
cancer tissues, and that miR-29s directly target both DNMT3A and -3B. The 
enforced expression of miR-29s in lung cancer cell lines restores normal 
patterns of DNA methylation, induces reexpression of methylation-silenced tumor 
suppressor genes, such as FHIT and WWOX, and inhibits tumorigenicity in vitro 
and in vivo. These findings support a role of miR-29s in epigenetic 
normalization of NSCLC, providing a rationale for the development of miRNA-based 
strategies for the treatment of lung cancer.