In this study, we report for the first time reduced expression of the let-7 microRNA in human lung cancers. Interestingly, 143 lung cancer cases that had undergone potentially curative resection could be classified into two major groups according to let-7 expression in unsupervised hierarchical analysis, showing significantly shorter survival after potentially curative resection in cases with reduced let-7 expression (P ‫؍‬ 0.0003). Multivariate COX regression analysis showed this prognostic impact to be independent of disease stage (hazard ratio ‫؍‬ 2.17; P ‫؍‬ 0.009). In addition, overexpression of let-7 in A549 lung adenocarcinoma cell line inhibited lung cancer cell growth in vitro. This study represents the first report of reduced expression of let-7 and the potential clinical and biological effects of such a microRNA alteration.

MicroRNAs (miRNAs) are small noncoding RNAs, thought to be involved in physiologic and developmental processes by negatively regulating expression of target genes. We have previously reported frequent down-regulation of the let-7 miRNA family in lung cancers and, in the present study, assessed alteration in a panel of 19 lung cancer cell lines. As a result, we found for the first time that the miR-17-92 cluster, which comprises seven miRNAs and resides in intron 3 of the C13or f 25 gene at 13q31.3, is markedly overexpressed in lung cancers, especially with small-cell lung cancer histology. Southern blot analysis revealed the presence of increased gene copy numbers of the miRNA cluster in a fraction of lung cancer cell lines with overexpression. In addition, we were able to show predominant localization of C13orf 25 transcripts within the nucleus and introduction of the expression construct of the miR-17-92 cluster, but not the putative open reading frame of C13orf 25, enhancing lung cancer cell growth. These findings clearly suggest that marked overexpression of the miR-17-92 cluster with occasional gene amplification may play a role in the development of lung cancers, especially in their most aggressive form, small-cell lung cancer, and that the C13orf 25 gene may well be serving as a vehicle in this regard. (Cancer Res 2005; 65(21): 9628-32)

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Emerging evidence suggests that microRNA, which are wellconserved, abundant and small regulatory RNA, may be involved in the pathogenesis of human cancers. We recently reported that expression of let-7 was frequently reduced in lung cancers, and that reduced let-7 expression was significantly associated with shorter patient survival. Two members of the double-stranded RNA-specific endonuclease family, Dicer and Drosha, convert precursor forms of microRNA into their mature forms using a stepwise process. In the present study, we examined expression levels of these genes in 67 non-small cell lung cancer cases, and found for the first time that Dicer expression levels were reduced in a fraction of lung cancers with a significant prognostic impact on the survival of surgically treated cases. It should be noted that multivariate COX regression analysis showed that the prognostic impact of Dicer (P = 0.001) appears to be independent of disease stage (P = 0.001), while logistic regression analysis demonstrated that the higher incidence of reduced Dicer expression in poorly differentiated tumors remained significant even after correction for other parameters (P = 0.02).