A list of authors and their affiliations appears at the end of the paperWe present a draft genome sequence of the platypus, Ornithorhynchus anatinus. This monotreme exhibits a fascinating combination of reptilian and mammalian characters. For example, platypuses have a coat of fur adapted to an aquatic lifestyle; platypus females lactate, yet lay eggs; and males are equipped with venom similar to that of reptiles. Analysis of the first monotreme genome aligned these features with genetic innovations. We find that reptile and platypus venom proteins have been co-opted independently from the same gene families; milk protein genes are conserved despite platypuses laying eggs; and immune gene family expansions are directly related to platypus biology. Expansions of protein, non-protein-coding RNA and microRNA families, as well as repeat elements, are identified. Sequencing of this genome now provides a valuable resource for deep mammalian comparative analyses, as well as for monotreme biology and conservation.

Pancreatic cancer is a highly aggressive malignancy due to elevated mitotic activities and epithelial-mesenchymal transition (EMT). Oncogenic RAS and transforming growth factor-␤ signaling are implicated in these malignant features. The mechanisms that underlie EMT need to be addressed since it promotes tissue invasion and metastasis. The high-mobility group A protein 2 (HMGA2) is a non-histone chromatin factor that is primarily expressed in undifferentiated tissues and tumors of mesenchymal origin. However, its role in EMT in pancreatic cancer is largely unknown. Here we report that HMGA2 is involved in EMT maintenance in human pancreatic cancer cells. Specific knockdown of HMGA2 inhibited cell proliferation, leading to an epithelial-state transition that restores cell-cell contact due to E-cadherin up-regulation. Consistently, an inverse correlation between HMGA2-positive cells and E-cadherin-positive cells was found in cancer tissues. Inhibition of the RAS/ MEK pathway also induced an epithelial transition, together with HMGA2 down-regulation. Transcriptional repressors of the E-cadherin gene, such as SNAIL, decreased after HMGA2 knockdown since HMGA2 directly activated the SNAlL gene promoter. The decrease of SNAIL after RAS/MEK inhibition was suppressed by HMGA2 overexpression. Further, let-7 microRNA-mediated HMGA2 down-regulation had no effect on the prevention of the transformed phenotype in these cells. These data shed light on the importance of HMGA2 in reversibly maintaining EMT, suggesting that HMGA2 is a potential therapeutic target for the treatment of pancreatic cancer. Pancreatic cancer has the poorest prognosis among human neoplasms due to its highly aggressive and metastasizing features.1-3 Current diagnostic tools have difficulty in detecting the early stage of this disease, and therapeutic applications often remain ineffective at advanced stages. Thus, the mechanisms leading to progression of this cancer especially need to be understood at molecular levels. The epithelial-mesenchymal transition (EMT) is a physiological process, originally found in embryonic development, in which the cells lose epithelial characteristics and gain mesenchymal properties. 4 This process is accompanied by loss of cell-to-cell contact and subsequent increased cell movement. Recent reports have implicated EMT in a malignant conversion of transformed cells, which represents invasive or metastasizing properties in a variety of cancers. 5,6 In pancreatic cancer cells, EMT is also reported to be a crucial step for tumor cell migration and invasion.7 Previous studies suggest that aberrations in pathways emerging from oncogenic RAS and transforming growth factor-␤ (TGF-␤) stimulate the malignant features, including EMT.6,8 Several transcriptional factors have been identified that control EMT by repressing E-cadherin and other epithelial genes in embryonic morphogenesis and cancer metastasis.6,9 These include the Snail-related zinc-finger factors (SNAIL and SLUG), the other zinc-finger factors (SIP1/ZEB2 and ZEB1/␦EF-1), ...

No abstract

The development of stomach cancer is closely associated with chronic inflammation, and the Wnt/␤-catenin signaling pathway is activated in most cases of this cancer. High-mobility group A (HMGA) proteins are oncogenic chromatin factors that are primarily expressed not only in undifferentiated tissues but also in various tumors. Here we report that HMGA1 is induced by the Wnt/␤-catenin pathway and maintains proliferation of gastric cancer cells. Specific knockdown of HMGA1 resulted in marked reduction of cell growth. The loss of ␤-catenin or its downstream c-myc decreased HMGA1 expression, whereas Wnt3a treatment increased HMGA1 and c-myc transcripts. Furthermore , Wnt3a-induced expression of HMGA1 was inhibited by c-myc knockdown, suggesting that HMGA1 is a downstream target of the Wnt/␤-catenin pathway. Enhanced expression of HMGA1 coexisted with the nuclear accumulation of ␤-catenin in about 30% of gastric cancer tissues. To visualize the expression of HMGA1 in vivo, transgenic mice expressing endogenous HMGA1 fused to enhanced green fluorescent protein were generated and then crossed with K19-Wnt1/C2mE mice, which develop gastric tumors through activation of both the Wnt and prostaglandin E2 pathways. Expression of HMGA1-enhanced green fluorescent protein was normally detected in the forestomach, along the upper border of the glandular stomach, but its expression was also up-regulated in cancerous glandular stomach. These data suggest that HMGA1 is involved in proliferation and gastric tumor formation via the Wnt/␤-catenin pathway. (Am J

No abstract