MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by interacting with the 3′ untranslated region (3′-UTR) of multiple mRNAs. Recent studies have linked miRNAs to the development of cancer metastasis. In this study, we show that miR-194 is specifically expressed in the human gastrointestinal tract and kidney. Moreover, miR-194 is highly expressed in hepatic epithelial cells, but not in Kupffer cells or hepatic stellate cells, two types of mesenchymal cells in the liver. miR-194 expression was decreased in hepatocytes cultured in vitro, which had undergone a dedifferentiation process. Furthermore, expression of miR-194 was low in liver mesenchymal-like cancer cell lines. The overexpression of miR-194 in liver mesenchymal-like cancer cells reduced the expression of the mesenchymal cell marker N-cadherin and suppressed invasion and migration of the mesenchymal-like cancer cells both in vitro and in vivo. We further demonstrated that miR-194 targeted the 3′-UTRs of several genes that were involved in epithelial-mesenchymal transition and cancer metastasis. Conclusion: These results support a role of miR-194, which is specifically expressed in liver parenchymal cells, in preventing liver cancer cell metastasis.
The emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic, leading to millions of infections and hundreds of thousands of human deaths. The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses, although the viral proteins responsible for this immune evasion are not clear. In this study, we identified SARS-CoV-2 structural proteins, accessory proteins, and the main viral protease as potent inhibitors of host innate immune responses of distinct pathways. In particular, the main viral protease was a potent inhibitor of both the RLR and cGAS-STING pathways. Viral accessory protein ORF3a had the unique ability to inhibit STING, but not the RLR response. On the other hand, structural protein N was a unique RLR inhibitor. ORF3a bound STING in a unique fashion and blocked the nuclear accumulation of p65 to inhibit nuclear factor-κB signaling. 3CL of SARS-CoV-2 inhibited K63-ubiquitin modification of STING to disrupt the assembly of the STING functional complex and downstream signaling. Diverse vertebrate STINGs, including those from humans, mice, and chickens, could be inhibited by ORF3a and 3CL of SARS-CoV-2. The existence of more effective innate immune suppressors in pathogenic coronaviruses may allow them to replicate more efficiently in vivo. Since evasion of host innate immune responses is essential for the survival of all viruses, our study provides insights into the design of therapeutic agents against SARS-CoV-2.
Farnesoid X receptor (FXR) (nuclear receptor subfamily 1, group H, member 4) is a member of nuclear hormone receptor superfamily, which plays essential roles in metabolism of bile acids, lipid, and glucose. We previously showed spontaneously hepatocarcinogenesis in aged FXR(-/-) mice, but its relevance to human hepatocellular carcinoma (HCC) is unclear. Here, we report a systematical analysis of hepatocarcinogenesis in FXR(-/-) mice and FXR expression in human liver cancer. In this study, liver tissues obtained from FXR(-/-) and wild-type mice at different ages were compared by microarray gene profiling, histological staining, chemical analysis, and quantitative real-time PCR. Primary hepatic stellate cells and primary hepatocytes isolated from FXR(-/-) and wild-type mice were also analyzed and compared. The results showed that the altered genes in FXR(-/-) livers were mainly related to metabolism, inflammation, and fibrosis, which suggest that hepatocarcinogenesis in FXR(-/-) mice recapitulated the progression of human liver cancer. Indeed, FXR expression in human HCC was down-regulated compared with normal liver tissues. Furthermore, the proinflammatory cytokines, which were up-regulated in human HCC microenvironment, decreased FXR expression by inhibiting the transactivity of hepatic nuclear factor 1α on FXR gene promoter. Our study thereby demonstrates that the down-regulation of FXR has an important role in human hepatocarcinogenesis and FXR(-/-) mice provide a unique animal model for HCC study.
APOBEC3G (A3G) and related cytidine deaminases, such as APOBEC3F (A3F), are potent inhibitors of retroviruses. Formation of infectious human immunodeficiency virus type 1 (HIV-1) requires suppression of multiple cytidine deaminases by Vif. Whether HIV-1 Vif recognizes various APOBEC3 proteins through a common mechanism is unclear. The domains in Vif that mediate APOBEC3 recognitions are also poorly defined. The N-terminal region of HIV-1 Vif is unusually rich in Trp residues, which are highly conserved. In the present study, we examined the role of these Trp residues in the suppression of APOBEC3 proteins by HIV-1 Vif. We found that most of the highly conserved Trp residues were required for efficient suppression of both A3G and A3F, but some of these residues were selectively required for the suppression of A3F but not A3G. Mutant Vif molecules in which Ala was substituted for Trp79 and, to a lesser extent, for Trp11 remained competent for A3G interaction and its suppression; however, they were defective for A3F interaction and therefore could not efficiently suppress the antiviral activity of A3F. Interestingly, while the HIV-1 Vif-mediated degradation of A3G was not affected by the different C-terminal tag peptides, that of A3F was significantly influenced by its C-terminal tags. These data indicate that the mechanisms by which HIV-1 Vif recognizes its target molecules, A3G and A3F, are not identical. The fact that several highly conserved residues in Vif are required for the suppression of A3F but not that of A3G suggests a critical role for A3F in the restriction of HIV-1 in vivo.APOBEC3G (A3G) and the related cytidine deaminase APOBEC3F (A3F) are potent inhibitors of a wide range of retroviruses and retroelements (2,
Shp2 tyrosine phosphatase plays a critical role in hematopoiesis, and dominant active mutations have been detected in the human gene PTPN11, encoding Shp2, in child leukemia patients. We report here that although no such mutations were detected in 44 adult leukemia patients screened, Shp2 expression levels were significantly elevated in primary leukemia cells and leukemia cell lines, as compared with normal hematopoietic progenitor cells. The Shp2 protein amounts correlated well with the hyperproliferative capacity but were inversely associated with the differentiation degree of leukemia cells. Suppression of Shp2 expression induced apoptosis and inhibition of leukemic cell clonogenic growth. Notably, the majority of Shp2 was preferentially localized to the plasma membrane and was constitutively phosphorylated on tyrosine in leukemia cells, and also in normal hematopoietic cells following mitogenic stimulation. Based on these results, we propose that aberrantly increased expression of Shp2 may contribute, collaboratively with other factors, to leukemogenesis. IntroductionThe Src homology 2 (SH2) domain containing phosphotyrosine phosphatase 2 (Shp2), a ubiquitously expressed enzyme, plays a crucial role in normal hematopoietic cell development. [1][2][3] In vitro hematopoietic differentiation assay showed a severe suppression of erythroid/myeloid progenitor cell development from homozygous mutant (Shp2 ⌬46-110 ) embryonic stem (ES) cells. 1 Consistently, neither erythroid nor myeloid progenitor cells of Shp2 ⌬46-110 origin were detectable in the fetal liver or bone marrow of chimeric animals that were derived from aggregation of mutant ES cells and wild-type embryos, although a significant contribution of mutant cells was observed in a few other organs or tissue of the chimeras. 2 Subsequent experiments using the Rag-2 (recombination activating protein-2)-deficient blastocyst complementation assay demonstrated a function of Shp2 for lymphopoiesis in a cell-autonomous manner, and differentiation of lymphoid cell lineages in Shp2 Ϫ/Ϫ / Rag-2 Ϫ/Ϫ chimeric mice was blocked before pro-T-and pro-B-cell stages. 4 Together, these observations suggest a stringent requirement for a functional Shp2 in normal hematopoietic cell development in mammals.Upon stimulation of factor-dependent cell lines with interleukin-6 (IL-6), leukemia inhibitory factor (LIF), IL-3/granulocyte macrophage-colony-stimulating factor (GM-CSF), or erythropoietin (Epo), Shp2 rapidly becomes tyrosine-phosphorylated. 5,6 Cells expressing a mutant gp130 that results in elimination of tyrosine phosphorylation fail to proliferate upon ligand stimulation. 7 Shp2 appears to play a positive role in activation of Akt and Erk signaling pathways, which promote cell proliferation/ survival and block cell apoptosis, critical events in tumorigenesis. [8][9][10] Functional analysis suggested that Shp2 may act in both catalytic-dependent and -independent manners in mediating IL-3-stimulated proliferation and survival of hematopoietic cells. 11 Several studies have...
Bcr-Abl tyrosine kinase inhibitors (TKIs) have been a remarkable success for the treatment of Ph ؉ chronic myeloid leukemia (CML). However, a significant proportion of patients treated with TKIs develop resistance because of leukemia stem cells (LSCs) and T315I mutant Bcr-Abl. Here we describe the unknown activity of the natural product berbamine that efficiently eradicates LSCs and T315I mutant BcrAbl clones. Unexpectedly, we identify CaMKII ␥ as a specific and critical target of berbamine for its antileukemia activity. Berbamine specifically binds to the ATPbinding pocket of CaMKII ␥, inhibits its phosphorylation and triggers apoptosis of leukemia cells. More importantly, CaMKII ␥ is highly activated in LSCs but not in normal hematopoietic stem cells and coactivates LSC-related -catenin and Stat3 signaling networks. The identification of CaMKII ␥ as a specific target of berbamine and as a critical molecular switch regulating multiple LSC-related signaling pathways can explain the unique antileukemia activity of berbamine. These findings also suggest that berbamine may be the first ATP-competitive inhibitor of CaMKII ␥, and potentially, can serve as a new type of molecular targeted agent through inhibition of the CaMKII ␥ activity for treatment of leukemia. (Blood. 2012; 120(24):4829-4839) IntroductionChronic myeloid leukemia (CML), which accounts for approximately 20% of all adult leukemias, 1 is characterized by the presence of the Philadelphia chromosome (Ph ϩ ), which results from a chromosomal translocation between the Bcr gene on chromosome 22 and the Abl gene on chromosome 9. 2 This translocation produces the fusion protein Bcr-Abl that has constitutive kinase activity 3 and is essential for the growth of CML cells and has become an attractive target for treatment of Ph ϩ CML cases, and the Abl tyrosine kinase inhibitors (TKIs) are now first-line therapeutic agents. [4][5][6] Inhibition of Bcr-Abl with Abl tyrosine kinase inhibitors (TKIs), such as imatinib (IM), is highly effective in controlling CML at chronic phase but not curing the disease. This is largely because of the inability of these kinase inhibitors to kill leukemia stem cells (LSCs) responsible for initiation, drug resistance, and relapse of CML 4-6 and Bcr-Abl gene mutation, particularly T315I mutant Bcr-Abl clones. 7-9 Thus, drug resistance associated with TKIs has created a need for more potent and safer therapies against other targets apart from the Bcr-Abl oncogenic kinase.Increasing evidence shows that traditional Chinese medicine (TCM) products not only play important roles in the discovery and development of drugs, but can also be used as molecular probes for identifying therapeutic targets. Homoharringtonine, arsenic trioxide, and triptolide are 3 famous examples. 9-11 Berbamine (BBM) is a structurally unique bisbenzylisoquinoline isolated from TCM Berberis amurensis, and has been used in traditional Chinese medicine for treating a variety of diseases from inflammation to tumors for many years. 12,13 It possesses a unique profile ...
The amino-terminal region of the Vif molecule in human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV) contains a conserved SLV/Ix4Yx9Y motif that was first described in 1992, but the importance of this motif for Vif function has not yet been examined. Our characterization of the amino acids surrounding this motif in HIV-1 Vif indicated that the region is critical for APOBEC3 suppression. In particular, amino acids K22, K26, Y30, and Y40 were found to be important for the Vif-induced degradation and suppression of cellular APOBEC3G (A3G). However, mutation of these residues had little effect on the Vif-mediated suppression of A3F, A3C, or A3DE, suggesting that these four residues are not important for Vif assembly with the Cul5 E3 ubiquitin ligase or protein folding in general. The LV portion of the Vif SLV/Ix4 Yx9Y motif was found to be required for optimal suppression of A3F, A3C, or A3DE. Human cytidine deaminase apolipoprotein B mRNA-editing catalytic polypeptide-like 3G (APOBEC3G, here called A3G) and related APOBEC3 proteins are potent inhibitors of diverse viruses and endogenous retroelements (2,9,11,13,18,30,42,47,48,63,72). The Vif protein of human immunodeficiency virus type 1 (HIV-1) and related viruses provides a viral defense against A3G and other APOBEC3 proteins, allowing infection and replication to proceed in host cells. In the absence of the Vif protein, however, A3G is packaged into HIV-1 particles through its interaction with viral Gag molecules (1,7,12,27,41,51,75), with the help of cellular and/or viral genomic RNAs (5,22,61,65,75). Virion-associated A3G induces C-to-U mutations in the newly synthesized viral minusstrand DNA (17,24,31,33,60,71,76) and reduces the accumulation of viral reverse transcripts (3,16,21,28,36,54,70) and the formation of proviral DNA (28, 36) through both deamination-dependent (40, 55) and -independent (4, 43) mechanisms.HIV-1 Vif overcomes the antiviral activity of APOBEC3 by assembling with the components of the cellular cullin 5 (Cul5)-elongin B-elongin C E3 ubiquitin ligase complex (73) to target A3G for proteasomal degradation (10,25,26,35,37,56,59,73). Vif molecules of HIV/simian immunodeficiency virus (SIV) interact with Cul5 using a highly conserved Hx 5 Cx [17][18]
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