MicroRNAs (miRNAs) are an abundant class of small noncodingRNAs that function as negative gene regulators. miRNA deregulation is involved in the initiation and progression of human cancer; however, the underlying mechanism and its contributions to genome-wide transcriptional changes in cancer are still largely unknown. We studied miRNA deregulation in human epithelial ovarian cancer by integrative genomic approach, including miRNA microarray (n ‫؍‬ 106), array-based comparative genomic hybridization (n ‫؍‬ 109), cDNA microarray (n ‫؍‬ 76), and tissue array (n ‫؍‬ 504). miRNA expression is markedly down-regulated in malignant transformation and tumor progression. Genomic copy number loss and epigenetic silencing, respectively, may account for the downregulation of Ϸ15% and at least Ϸ36% of miRNAs in advanced ovarian tumors and miRNA down-regulation contributes to a genome-wide transcriptional deregulation. Last, eight miRNAs located in the chromosome 14 miRNA cluster (Dlk1-Gtl2 domain) were identified as potential tumor suppressor genes. Therefore, our results suggest that miRNAs may offer new biomarkers and therapeutic targets in epithelial ovarian cancer.Dlk1-Gtl2 domain ͉ noncoding RNA

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Mucinous adenocarcinoma of the lung is a subtype of highly invasive pulmonary tumors and is associated with decreased or absent expression of the transcription factor NK2 homeobox 1 (NKX2-1; also known as TTF-1). Here, we show that haploinsufficiency of Nkx2-1 in combination with oncogenic Kras G12D , but not with oncogenic EGFR L858R , caused pulmonary tumors in transgenic mice that were phenotypically similar to human mucinous adenocarcinomas. Gene expression patterns distinguished tumor goblet (mucous) cells from nontumorigenic airway and intestinal goblet cells. Expression of NKX2-1 inhibited urethane and oncogenic Kras G12D -induced tumorigenesis in vivo. Haploinsufficiency of Nkx2-1 enhanced Kras G12D -mediated tumor progression, but reduced EGFR L858R -mediated progression. Genome-wide analysis of gene expression demonstrated that a set of genes induced in mucinous tumors was shared with genes induced in a nontumorigenic chronic lung disease, while a distinct subset of genes was specific to mucinous tumors. ChIP with massively parallel DNA sequencing identified a direct association of NKX2-1 with the genes induced in mucinous tumors. NKX2-1 associated with the AP-1 binding element as well as the canonical NKX2-1 binding element. NKX2-1 inhibited both AP-1 activity and tumor colony formation in vitro. These data demonstrate that NKX2-1 functions in a context-dependent manner in lung tumorigenesis and inhibits Kras G12D -driven mucinous pulmonary adenocarcinoma. IntroductionMucinous adenocarcinoma of the lung (formerly known as mucinous bronchioalveolar cancer) is pathologically classified as tumor cells with goblet cell morphology containing abundant intracytoplasmic mucin (1). Invasive mucinous adenocarcinoma of the lung has a higher malignant potential than do the more common types of lung adenocarcinoma, such as acinar or papillary adenocarcinoma. Mucinous adenocarcinoma of the lung is associated with decreased or absent expression of the transcription factor NK2 homeobox 1 (NKX2-1; also known as TTF-1) and the expression of mucins, including mucin 5AC, oligomeric mucus/gel-forming (MUC5AC). Genetically, approximately 76% of mucinous adenocarcinomas of the lung have KRAS mutations, a frequent mutation in lung adenocarcinoma associated with tobacco use (2), but mucinous adenocarcinoma of the lung is rarely associated with EGFR mutations. In contrast, nonmucinous lung adenocarcinoma is frequently associated with EGFR mutations (∼45%), but less frequently with KRAS mutations (∼13%; ref. 1).NKX2-1 plays a critical role in lung morphogenesis and respiratory epithelial-specific gene expression, including activation of surfactant proteins and repression of mucins (3, 4). The potential oncogenic role of NKX2-1 in the pathogenesis of adenocarcinoma of the lung was proposed by findings that a region of 14q13.3 containing NKX2-1, NKX2-8, and PAX9 was amplified in approximately 10% of human lung adenocarcinoma (5-7). Loss-offunction and gain-of-function studies in human lung carcinoma and transformed cells supporte...

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SUMMARY:Degradation of basement membrane and extracellular matrix structures are important features of the metastatic process of malignant tumors. Human heparanase degrades heparan sulfate proteoglycans, which represent the main components of basement membranes and the extracellular matrix. Because of the role of heparanase in tumor invasion and metastasis, we examined heparanase expression in primary gastric cancers and in cell lines derived from gastric cancers by immunohistochemistry and RT-PCR, respectively. Four of seven gastric cancer cell lines showed heparanase mRNA expression by RT-PCR. Heparanase protein was detected in both the cytoplasm and the nucleus of heparanase mRNA-positive cells by immunohistochemical staining. Heparanase expression was confirmed in 35 (79.5%) of 44 gastric tumor samples by immunohistochemical staining. However, no or weak heparanase expression was detected in normal gastric mucosa. In situ hybridization showed that the mRNA expression pattern of heparanase was similar to that of the protein, suggesting that increased expression of the heparanase protein at the invasive front was caused by an increase of heparanase mRNA in tumor cells. Analysis of the clinicopathologic features showed stronger heparanase expression in cases of huge growing tumors, extensive invasion to lymph vessels, and regional lymph node metastasis. In gastric cancer, patients with heparanase expression showed significantly poorer prognosis than those without such expression (p ϭ 0.006). In conclusion, our findings suggest that high expression of heparanase in gastric cancer is a strong predictor of poor survival. (Lab Invest 2003, 83:613-622).

Background & Aims-Esophageal squamous cell carcinoma (ESCC) is known to be a highly angiogenic tumor. Here, we investigate the role of the stromal fibroblasts in the ESCC-induced angiogenic response using a novel 3D model.

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