Background: Glioblastoma multiforme (GBM) is an invariably fatal central nervous system tumor despite treatment with surgery, radiation, and chemotherapy. Further insights into the molecular and cellular mechanisms that drive GBM formation are required to improve patient outcome. MicroRNAs are emerging as important regulators of cellular differentiation and proliferation, and have been implicated in the etiology of a variety of cancers, yet the role of microRNAs in GBM remains poorly understood. In this study, we investigated the role of microRNAs in regulating the differentiation and proliferation of neural stem cells and glioblastoma-multiforme tumor cells.

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Spiders produce a variety of silks that range from Lycra-like elastic fibers to Kevlar-like superfibers. A gene family from the spider Araneus diadematus was found to encode silk-forming proteins (fibroins) with different proportions of amorphous glycine-rich domains and crystal domains built from poly(alanine) and poly(glycine-alanine) repeat motifs. Spiders produce silks of different composition by gland-specific expression of this gene family, which allows for a range of mechanical properties according to the crystal-forming potential of the constituent fibroins. These principles of fiber property control may be important in the development of genetically engineered structural proteins.

Purpose: This study was designed to elucidate the role of amplification at 8q24 in the pathophysiology of ovarian and breast cancer because increased copy number at this locus is one of the most frequent genomic abnormalities in these cancers. Experimental Design:To accomplish this, we assessed the association of amplification at 8q24 with outcome in ovarian cancers using fluorescence in situ hybridization to tissue microarrays and measured responses of ovarian and breast cancer cell lines to specific small interfering RNAs against the oncogene MYC and a putative noncoding RNA, PVT1, both of which map to 8q24. Results: Amplification of 8q24 was associated with significantly reduced survival duration. In addition, small interfering RNA^mediated reduction in either PVT1 or MYC expression inhibited proliferation in breast and ovarian cancer cell lines in which they were both amplified and overexpressed but not in lines in which they were not amplified/overexpressed. Inhibition of PVT1 expression also induced a strong apoptotic response in cell lines in which it was overexpressed but not in lines in which it was not amplified/overexpressed. Inhibition of MYC, on the other hand, did not induce an apoptotic response in cell lines in which MYC was amplified and overexpressed. Conclusions: These results suggest that MYC and PVT1 contribute independently to ovarian and breast pathogenesis when overexpressed because of genomic abnormalities. They also suggest that PVT1-mediated inhibition of apoptosis may explain why amplification of 8q24 is associated with reduced survival duration in patients treated with agents that act through apoptotic mechanisms.Amplification of a region on chromosome 8q24 is one of the most frequent events in carcinomas, including serous ovarian and breast cancers, and has been associated with reduced survival duration in some studies (1, 2). The well-established oncogene MYC maps to this locus and likely contributes to the pathophysiology of cancers in which it is amplified. However, the PVT1 transcript also maps to this region and has been implicated in cancer pathophysiology as well (3). In mouse, for example, the pvt-1 locus is a site of recurrent translocation in plasmacytomas (4, 5) and is a common site of tumorigenic retroviral insertion in lymphomas (6). In humans, the region homologous to pvt-1 is a site of recurrent translocation between chromosomes 2 and 8 (7, 8) and its first exon is coamplified with MYC in colon carcinoma cell lines (9). PVT1 has been suggested as a MYC activator (10); however, little evidence exists to support that role. Moreover, evidence is now emerging that PVT1 may act as a noncoding RNA 12 that is strongly conserved between mouse and human.We now present evidence that both PVT1 and MYC contribute to ovarian and breast cancer pathophysiology when 12 Huppi et al., personal communication.

Hypoxia-inducible factor-1␣ (HIF-1␣) transactivates genes required for energy metabolism and tissue perfusion and is necessary for embryonic development and tumor explant growth. HIF-1␣ is overexpressed during carcinogenesis, myocardial infarction, and wound healing; however, the biological consequences of HIF-1␣ overexpression are unknown. Here, transgenic mice expressing constitutively active HIF-1␣ in epidermis displayed a 66% increase in dermal capillaries, a 13-fold elevation of total vascular endothelial growth factor (VEGF) expression, and a six-to ninefold induction of each VEGF isoform. Despite marked induction of hypervascularity, HIF-1␣ did not induce edema, inflammation, or vascular leakage, phenotypes developing in transgenic mice overexpressing VEGF cDNA in skin. Remarkably, blood vessel leakage resistance induced by HIF-1␣ overexpression was not caused by up-regulation of angiopoietin-1 or angiopoietin-2. Hypervascularity induced by HIF-1␣ could improve therapy of tissue ischemia.