Understanding hub genes involved in gastric cancer (GC) metastasis could lead to effective approaches to diagnose and treat cancer metastasis. In this study, 272 differentially expressed genes between synchronous liver metastasis and the paired GC were selected from microarray assays. KEGG pathway analysis indicated that of 13 enriched pathways, 8 were involved in cancer metastasis. Literature-based annotations showed that the differentially expressed genes significantly enriched known metastasisrelated genes. With the use of protein-protein interaction network, we found a subnetwork significantly enriching the metastasis-related genes and hubs. Unannotated hubs in this subnetwork were predicted to be novel metastasis-associated genes. Nine hubs in this subnetwork were validated by using quantitative RT-PCR, and 4 hubs were further validated by immunohistochemistry. NR4A2 was significantly down-regulated in synchronous liver metastasis compared with the paired GC at both transcriptional and translational levels. NR4A2 immunostaining was apparent in the mesenchymal cells of pathologically normal gastric mucosa and in the epithelial cells of primary GC. HSP90AA1 was not only up-regulated in the metastatic GC compared with primary GC at both transcriptional and translational levels, but also up-regulated in primary GC compared with the normal mucosa at the translational level. NR4A2, NR3C1, ARF3, XAB2, and alternatively spliced variants of NR4A2, SP8 and SP-novel, were significantly down-regulated, whereas CCNE1 significantly up-regulated, in primary GC compared with the normal gastric mucosa. Conclusively, NR4A2 and HSP90AA1 stand out as promising diagnostic markers and therapeutic targets for liver metastasis of GC. CCNE1 and NR3C1 indicate primary GC, rather than distant metastasis. ' 2009 UICC

Rationale: Long extracellular RNAs (exRNAs) in plasma can be profiled by new sequencing technologies, even with low abundance. However, cancer-related exRNAs and their variations remain understudied. Methods: We investigated different variations (i.e. differential expression, alternative splicing, alternative polyadenylation, and differential editing) in diverse long exRNA species (e.g. long noncoding RNAs and circular RNAs) using 79 plasma exosomal RNA-seq (exoRNA-seq) datasets of multiple cancer types. We then integrated 53 exoRNA-seq datasets and 65 self-profiled cell-free RNA-seq (cfRNA-seq) datasets to identify recurrent variations in liver cancer patients. We further combined TCGA tissue RNA-seq datasets and validated biomarker candidates by RT-qPCR in an individual cohort of more than 100 plasma samples. Finally, we used machine learning models to identify a signature of 3 noncoding RNAs for the detection of liver cancer. Results: We found that different types of RNA variations identified from exoRNA-seq data were enriched in pathways related to tumorigenesis and metastasis, immune, and metabolism, suggesting that cancer signals can be detected from long exRNAs. Subsequently, we identified more than 100 recurrent variations in plasma from liver cancer patients by integrating exoRNA-seq and cfRNA-seq datasets. From these datasets, 5 significantly up-regulated long exRNAs were confirmed by TCGA data and validated by RT-qPCR in an independent cohort. When using machine learning models to combine two of these validated circular and structured RNAs ( SNORD3B-1, circ-0080695 ) with a miRNA ( miR-122 ) as a panel to classify liver cancer patients from healthy donors, the average AUROC of the cross-validation was 89.4%. The selected 3-RNA panel successfully detected 79.2% AFP-negative samples and 77.1% early-stage liver cancer samples in the testing and validation sets. Conclusions: Our study revealed that different types of RNA variations related to cancer can be detected in plasma and identified a 3-RNA detection panel for liver cancer, especially for AFP-negative and early-stage patients.

AI~TRAC'r: The knowledge of contemporary climatic change over the Qinghai-Xizang (Tibet) Plateau (QXP) has been inadequate for a long time due to lack of enough observational data. In this paper, on the basis of monthly temperature and precipitation data in 1961 -1990 from 48 stations on the QXP, the temperature data are extended backward to 1901 with an empirical orthogonal function (EOF) method, microscopic characteristics of contemporary climatic change over the QXP are analyzed, and the response of the plateau climate to global wanning is discussed in combination with atmospheric general circulation model (G(M) outputs. The results show that the plateau climate, as a whole, has been warming since the early part of this century, that the precipitation has generally been increasing during the recent 30 years, and that these climatic trends seem to be related to the enhanced green-house effect induced by increasing CO2 concentration in the atmosphere.

Angiogenesis is a fundamental part of the response to tissue injury, which is involved in the development of hepatic fibrosis. Vascular endothelial growth factor plays an important role in angiogenesis. The expression of VEGF is increased during hepatic fibrogenesis and correlates with the micro-vessel density. In this study, we investigated the effects of bevacizumab, an anti-angiogenetic drug, on the formation of hepatic fibrosis. We found that bevacizumab could attenuate the development of hepatic fibrosis and contribute to the protection of liver function. Bevacizumab was also found to downregulate the expression α-SMA and TGF-β1, which have been reported to be profibrogenic genes in vivo. We also observed that the expression of VEGF increased significantly during the development of hepatic fibrosis and CCl4 was found to induce hepatocytes to secrete VEGF, which led to the activation and proliferation of HSCs. Bevacizumab was also found to block the effects of the hepatocytes on the activation and proliferation of HSCs. Our results suggest that bevacizumab might alleviate liver fibrosis by blocking the effect of VEGF on HSCs. Bevacizumab might be suitable as a potential agent for hepatic fibrosis therapy.

Substantial evidence indicates that transforming growth factor-beta 1 (TGF-β1) plays a vital role in epithelial-mesenchymal transition (EMT). PEG10 has been shown involved in invasion and metastasis of tumors. The present study investigated the role of PEG10 in TGF-β1-triggered EMT in hepatocellular carcinoma (HCC) progression. Immunohistochemistry and real-time PCR were used to measure the expression level of PEG10 in clinical HCC tissues with or without lymph node metastasis, and normal tissues. The results showed that PEG10 expression is higher in HCC tissues and associated with overall survival (OS) and lymph node metastasis. Moreover, PEG10 expression level was remarkably higher in hepatic cancer cells than the normal hepatic cell line L02. In the present study, we constructed an adenovirus vector containing the coding area of PEG10 (Ad-PEG10) and infected HepG2 cells and found that overexpression of PEG10 promoted the cell migration, invasion ability and EMT of HepG2 cells. TGF-β1 acted on HepG2 cells by enhancing cell migration, invasion, EMT and upregulating PEG10 expression level. However, cells pretreated with adenovirus vector of PEG10 shRNAs (Ad-shRNA1 and Ad-shRNA2) did not occur EMT prior to TGF-β1 stimulation. Moreover, TGF-β1 did not increase the migration and invasion of cells with PEG10 knockdown and overexpression of PEG10 confers chemoresistance to HepG2 cells. Accordingly, sufficient PEG10 expression level is essential for TGF-β1 induced EMT and associated with the chemoresistance in HepG2 cells.