We have investigated the changing rule of serum form of GP73 (sGP73) in different hepato-pathologic processes and identified the sGP73 role in inflammation, fibrosis and carcinogenesis since sGP73 has been regarded as a candidate tumor marker. Quantitative enzyme-linked immunosorbent assay detected sGP73 in 535 subjects with hepatocellular carcinoma (HCC), liver cirrhosis (LC), hepatitis, focal nodular hyperplasia (FNH), angioma, intra-hepatic cholangio-carcinoma (ICC) and metastatic cancer from adenocarcinomas (MC). Median sGP73 in LC was higher than in HCC and hepatitis (p 5 0.001), and sGP73 in all three groups were higher than those in healthy individuals (p < 0.001); sGP73 in LC patients with Child-Pugh class A was lower than in class B and C (p = 0.001), no significant difference was found between early and advanced HCC groups (110.4 lg/L vs. 102.8 lg/L). AFP/GP73 had a sensitivity of 75.8% and specificity of 79.7% with an area under the receiver operating curve (AUROC) of 0.844 vs. 0.812 for AFP (p 5 0.055) with a sensitivity of 95.2% and specificity of 47.1%; in detecting early HCC, AUROC of AFP/GP73 was 0. 804 vs. 0.766 for AFP (p 5 0.086). sGP73 correlated with AST, AST/ALT, ALB, A/G and ALP in LC. The positive rate of sGP73 in angioma, FNH, ICC, and MC was 0, 50, 63.3, 53.3%, respectively; AFP/GP73 was 0.796 with the sensitivity of 81.4% and specificity of 70.0% when differentiating MC from AFP-negative HCC. Increased sGP73 is related to hepatic impairment and chronic fibrosis, and when combined with AFP could improve the differential diagnosis of hepatic diseases.Primary hepatic cancers (PHC) have a high incidence worldwide and are lethal, with $10% surviving >5 years.

Tumor development has long been known to resemble abnormal embryogenesis. The ESC self-renewal gene NANOG is purportedly expressed in some epithelial cancer cells and solid tumors, but a casual role in tumor development has remained unclear. In order to more comprehensively elucidate the relationship between human Nanog and tumorigenesis, the hNanog was ectopically expressed in the 293 cell line to investigate its potential for malignant transformation of cells both in vitro and in vivo. Here we provide compelling evidence that the overexpression of hNanog resulted in increased cell proliferation, anchor-independent growth in soft agar, and formation of tumors after subcutaneous injection of athymic nude mice. Pathologic analysis revealed that these tumors were poorly differentiated. In analysis of the underlying molecular mechanism, two proteins, FAK and Ezrin, were identified to be upregulated in the hNanog expressing 293 cells. Our results demonstrate that hNanog is a potent human oncogene and has the ability to induce cellular transformation of human cells.

Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus. The nonstructural protein nsp5, also called 3C-like protease, is responsible for processing viral polyprotein precursors in coronavirus (CoV) replication. Previous studies have shown that PDCoV nsp5 cleaves the NF-κB essential modulator and the signal transducer and activator of transcription 2 to disrupt interferon (IFN) production and signaling, respectively. Whether PDCoV nsp5 also cleaves IFN-stimulated genes (ISGs), IFN-induced antiviral effector molecules, remains unclear. In this study, we screened 14 classical ISGs and found that PDCoV nsp5 cleaved the porcine mRNA-decapping enzyme 1a (pDCP1A) through its protease activity. Similar cleavage of endogenous pDCP1A was also observed in PDCoV-infected cells. PDCoV nsp5 cleaved pDCP1A at glutamine 343 (Q343), and the cleaved pDCP1A fragments, pDCP1A1–343 and pDCP1A344–580, were unable to inhibit PDCoV infection. Mutant pDCP1A-Q343A, which resists nsp5-mediated cleavage, exhibited a stronger ability to inhibit PDCoV infection than wild-type pDCP1A. Interestingly, the Q343 cleavage site is highly conserved in DCP1A homologs from other mammalian species. Further analyses demonstrated that nsp5 encoded by seven tested CoVs that can infect human or pig also cleaved pDCP1A and human DCP1A, suggesting that DCP1A may be the common target for cleavage by nsp5 of mammalian CoVs. IMPORTANCE Interferon (IFN)-stimulated gene (ISG) induction through IFN signaling is important to create an antiviral state and usually directly inhibits virus infection. The present study first demonstrated that PDCoV nsp5 can cleave mRNA-decapping enzyme 1a (DCP1A) to attenuate its antiviral activity. Furthermore, cleaving DCP1A is a common characteristic of nsp5 proteins from different coronaviruses (CoVs), which represents a common immune evasion mechanism of CoVs. Previous evidence showed that CoV nsp5 cleaves the NF-κB essential modulator and signal transducer and activator of transcription 2. Taken together, CoV nsp5 is a potent IFN antagonist because it can simultaneously target different aspects of the host IFN system, including IFN production and signaling and effector molecules.

Protein arginine methyltransferase 5 interacts with and methylates apoptosis signal–regulating kinase 1 at arginine residue 89, thereby negatively regulating its activity by promoting the interaction between ASK1 and Akt and thus phosphorylating ASK1 at serine residue 83.

Previously, we investigated the induction effect of LRP16 expression by estrogen (17b-estradiol, E 2 ) and established a feed-forward mechanism that activated estrogen receptor a (ERa) transactivation in estrogen-dependent epithelial cancer cells. LRP16 is required for ERa signaling transduction by functioning as an ERa coactivator. In this study, we demonstrated that LRP16 expression was upregulated in E 2 -responsive BG-1 ovarian cancer cells, but was downregulated in estrogen-resistant SKOV3 ovarian cancer cells. Pure estrogen antagonist ICI 182 780 did not affect LRP16 expression in SKOV3 cell. The unliganded ERa upregulated LRP16 expression and enhanced LRP16 promoter activity in SKOV3 cells; however, this induction was blocked by estrogen stimulation. Results from chromatin immunoprecipitation experiment revealed a strong recruitment of the unliganded ERa at LRP16 promoter in the absence of estrogen; however, ERa was largely released from the DNA upon E 2 stimulation. Modulation in LRP16 expression level did not significantly change the proliferation rate of SKOV3 cells and the growth responsiveness of cells to E 2 . Knockdown of LRP16 by RNA interference in SKOV3 cells markedly attenuated estrogen response elementdependent ERa reporter gene activity and E 2 -induced c-Myc expression. Our study suggests a novel mechanism of estrogen resistance of ovarian cancer by which estrogenrepressed signaling pathway antagonizes estrogen-activated signaling transduction.

Polo-like kinase 1 (Plk1) is a conserved serine/threonine protein kinase that plays pivotal roles during the cell cycle and cell proliferation. Although a number of important targets have been identified, the mechanism of Plk1-regulated pathways and the bulk of the Plk1 interactome are largely unknown. Here, we demonstrate that Plk1 interacts with the DExH/D RNA helicase, UAP56. The protein levels of UAP56 and Plk1 are inversely correlated during the cell cycle. We also show that Plk1 phosphorylates UAP56 in vitro and in vivo and that Plk1-dependent phosphorylation of UAP56 triggers ubiquitination and degradation of UAP56 through proteasomes. This result suggests that Plk1-mediated phosphorylation of UAP56 regulates the stability of UAP56. Our results will be helpful in further understanding mRNA metabolism, cell cycle progression, and the link between mRNA metabolism and cellular function.

Porcine deltacoronavirus (PDCoV), an emerging enteropathogenic coronavirus, causes diarrhoea in suckling piglets and has the potential for cross-species transmission. No effective PDCoV vaccines or antiviral drugs are currently available. Here, we successfully generated an infectious clone of PDCoV strain CHN-HN-2014 using a combination of bacterial artificial chromosome (BAC)-based reverse genetics system with a one-step homologous recombination. The recued virus (rCHN-HN-2014) possesses similar growth characteristics to the parental virus in vitro. Based on the established infectious clone and CRISPR/Cas9 technology, a PDCoV reporter virus expressing nanoluciferase (Nluc) was constructed by replacing the NS6 gene. Using two drugs, lycorine and resveratrol, we found that the Nluc reporter virus exhibited high sensibility and easy quantification to rapid antiviral screening. We further used the Nluc reporter virus to test the susceptibility of different cell lines to PDCoV and found that cell lines derived from various host species, including human, swine, cattle and monkey enables PDCoV replication, broadening our understanding of the PDCoV cell tropism range. Taken together, our reporter viruses are available to high throughput screening for antiviral drugs and uncover the infectivity of PDCoV in various cells, which will accelerate our understanding of PDCoV.

Members of the super-class of zinc finger proteins are key regulators in early embryogenesis. Utilizing in silico mining of EST Databases for pre-implantation Embryo-Specific Zinc Finger Protein Genes, we characterized a novel zygotic mouse gene-tripartite motif family-like 1 (TRIML1), which expresses in embryo before implantation. Knocking down of TRIML1 resulted in the fewer cell number of blastocysts and failture to give rise to neonates after embryo transfer. The binding partner of TRIML1, Ubiquitin-specific protease 5 (USP5), was identified by yeast two-hybrid screening assay. The interaction was confirmed by GST pull-down and coimmunoprecipitation analysis. The role of TRIML1 in ubiquitin pathway during the development stage of mouse blastocyst was further discussed.