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Rationale: Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung fibrosis with a high mortality rate. In organ repair and remodeling, epigenetic events are important. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and can target epigenetic molecules important in DNA methylation. The miR-17z92 miRNA cluster is critical for lung development and lung epithelial cell homeostasis and is predicted to target fibrotic genes and DNA methyltransferase (DNMT)-1 expression. Objectives: We investigated the miR-17z92 cluster expression and its role in regulating DNA methylation events in IPF lung tissue. Methods: Expression and DNA methylation patterns of miR-17z92 were determined in human IPF lung tissue and fibroblasts and fibrotic mouse lung tissue. The relationship between the miR-17z92 cluster and DNMT-1 expression was examined in vitro. Using a murine model of pulmonary fibrosis, we examined the therapeutic potential of the demethylating agent, 59-aza-29-deoxycytidine. Measurements and Main Results: Compared with control samples, miR17z92 expression was reduced in lung biopsies and lung fibroblasts from patients with IPF, whereas DNMT-1 expression and methylation of the miR-17z92 promoter was increased. Several miRNAs from the miR-17z92 cluster targeted DNMT-1 expression resulting in a negative feedback loop. Similarly, miR-17z92 expression was reduced in the lungs of bleomycin-treated mice. Treatment with 59-aza-29-deoxycytidine in a murine bleomycin-induced pulmonary fibrosis model reduced fibrotic gene and DNMT-1 expression, enhanced miR-17z92 cluster expression, and attenuated pulmonary fibrosis. Conclusions: This study provides insight into the pathobiology of IPF and identifies a novel epigenetic feedback loop between miR-17z92 and DNMT-1 in lung fibrosis.Keywords: microRNA; miR-17z92; pulmonary fibrosis; DNA methylation; DNMT-1 Idiopathic pulmonary fibrosis (IPF) represents the most aggressive form of interstitial lung disease with a median survival of 3-5 years (1). Failure to resolve epithelial cell injury in the lung is critical to the pathogenesis of IPF (2-4). In addition, epithelialmesenchymal transition (EMT) (5), fibroblast proliferation and activation (6), and recruitment of inflammatory cells (7,8) all contribute to extracellular matrix accumulation in the lung (7). The current study focused on identifying the molecular mechanisms underlying the pathogenesis of IPF.Because changes in fibrotic gene expression (2, 9-11) and few genetic mutations have been identified in IPF (12, 13), we focused on microRNA (miRNA, miR) expression and epigenetic regulators in lung epithelial cells and fibroblasts. MiRNAs can either block translation or degrade target mRNAs (14,15). Notably, a single miRNA can regulate upward of 30 genes. MiRNAs can be encoded in intronic or exonic DNA regions and encoded in their own open reading frame and controlled by DNA promoter elements, such as DNA methylation by DNA methyltransferases (DNMTs) of CpG islands (15,16). Of the three DNMTs expressed in h...

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MicroRNAs (miRNAs) are small 19- to 24-nt noncoding RNAs that have the capacity to regulate fundamental biological processes essential for cancer initiation and progression. In cancer, miRNAs may function as oncogenes or tumor suppressors. Here, we conducted global profiling for miRNAs in a cohort of stage 1 nonsmall cell lung cancers ( n = 81) and determined that miR-486 was the most down-regulated miRNA in tumors compared with adjacent uninvolved lung tissues, suggesting that miR-486 loss may be important in lung cancer development. We report that miR-486 directly targets components of insulin growth factor (IGF) signaling including insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and phosphoinositide-3-kinase, regulatory subunit 1 (alpha) (PIK3R1, or p85a) and functions as a potent tumor suppressor of lung cancer both in vitro and in vivo. Our findings support the role for miR-486 loss in lung cancer and suggest a potential biological link to p53.

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Over 400 cases of neuroendocrine (Merkel cell) carcinoma of the skin (NCS) have been reported. This tumor continues to pose problems in diagnosis and effective treatment for physicians unfamiliar with its biological characteristics. Reported here are five additional cases of NCS and the literature for this rare neoplasm is comprehensively reviewed. An early and accurate diagnosis is made possible by combining clinical presentation with results of histologic study, immunoperoxidase staining for neuron-specific enolase (NSE), epithelial membrane antigen (EMA), cytokeratins, and electron microscopy. NCS is an aggressive tumor. Depending on the length of follow-up, up to 40% of tumors locally recur, 55% develop regional nodal metastases, and 36% undergo distant metastasis. Survival is sex, but not age, dependent, with an overall 2-year survival rate of 72% (males 58% vs. females 79%). No standard procedure for initial and/or follow-up treatment for NCS exists. The authors recommend that NCS be treated, whenever possible, using the same rationale as applied for the treatment of squamous cell carcinoma of the skin.

The clinicopathologic features of 105 hepatoblastomas accessioned to the Armed Forces Institute of Pathology between 1967 and 1987 were reviewed. DNA content was analyzed by flow cytometry. A multivariate analysis using the Cox proportional hazards model was performed to evaluate the effect of stage, histologic type, and DNA content on the prognosis for survival. The relative risks of death for a given stage compared to the other stages combined were 0.1637, 0.5672, 2.8742, and 3.5148 for stages I-IV, respectively. The relative risk of death for a given histologic type adjusted for age, sex, and stage compared to the other types was 1.0739 (p = .8850) for the fetal pattern, 1.7409 (p = .1662) for the embryonal pattern, 0.5292 (p = .0754) for the mixed pattern, 1.1980 (p = .7729) for the macrotrabecular pattern, and 3.7096 (p = .1061) for the small-cell undifferentiated pattern. Of 19 hepatoblastomas analyzed for DNA content, 5 were DNA diploid and 11 were DNA aneuploid; 3 could not be classified. The stage of disease at presentation proved to be a significant prognostic factor, whereas histologic type and DNA content did not have a significant effect.

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