However, the role of miRNAs in SCLC pathogenesis has not been extensively studied. Our investigation identified a group of miRNAs that show a progressive differential expression from HBECs to NSCLC and SCLC cells. Several of the miRNAs identified in this study have been shown to be associated with various cancer types in previous studies. GSK2118436 nmr For BI-D1870 example, we found significant overexpression of miR-103, miR-107, miR-301 and miR-338 in lung cancer cells as compared to HBECs. These miRNAs have been shown to be over-expressed in several types of cancers including

lung cancers [17, 50, 51], and high expression of miR-103 and miR-107 were correlated with poor survival in cancer patients (esophageal squamous and pancreatic tumors) [51, 52]. These miRNAs might contribute to common pathways during the transformation of normal cells to tumor cells during lung cancer pathogenesis, and the greater extent of aberrant expression of these miRNAs in SCLCs relative to NSCLCs might contribute to the more aggressive phenotype of the former. Our study also identified a group of miRNAs that might contribute to the establishment of SCLC features and the specific phenotypes that differentiate SCLC from NSCLC. PF-02341066 order For example, we found over-expression of miR-17-5p in SCLCs compared to NSCLCs. This miRNA was recently shown to target Rbl2,

a member of the Rb family [53]. Rb is a tumor suppressor that induces arrest of the cell cycle at G1 [54]. SCLCs have been shown to exhibit loss of Rb expression in 87-100% of tumors compared to less than 15% in NSCLC [55–57]. SCLC cells were also previously shown to be addicted to continued over-expression of miR-17-5p [58], and forced over-expression of the miRNA cluster that includes miR-17-5p (miR-17-92)

was shown to induce embryonic lung epithelial cell proliferation [59]. Coupled with these data, our results suggest that dysregulation of this miRNA could be an important distinction that defines the pathogenesis and phenotypic characteristics of SCLC compared to NSCLC. We also observed a significant increase in miR-135 expression in SCLC cells compared to NSCLC cells. miR-135 has recently been shown to inhibit expression of the tumor suppressor gene Adenomatous Polyposis Resveratrol Coli (APC) in colorectal cancer [60]. Loss of heterozygosity of APC has been shown in both small cell and non-small cell lung cancers, but appears to be more frequent in SCLC [61]. Silencing of this gene by CpG hypermethylation, however, is more frequent in NSCLC compared to SCLC [62], suggesting that various lung tumor subtypes could use different means to down-regulate this tumor suppressor. These findings suggest that SCLC preferentially utilizes microRNA-based regulatory mechanisms to reduce APC expression. miR-29a, -29b and -29c expression was shown be significantly down-regulated in SCLC cells compared to HBECs, whereas these reductions were not seen in NSCLC cells.