Signal transducers and activators of transcription (STATs) comprise a family of cytoplasmic transcription factors that mediate intracellular signaling that is usually generated at cell surface receptors and thereby transmit it to the nucleus. Numerous studies have demonstrated constitutive activation of STAT3 in a wide variety of human tumors, including hematological malignancies (leukemias, lymphomas, and multiple myeloma) as well as diverse solid tumors (such as head and neck, breast, lung, gastric, hepatocellular, colorectal and prostate cancers). There is strong evidence to suggest that aberrant STAT3 signaling promotes initiation and progression of human cancers by either inhibiting apoptosis or inducing cell proliferation, angiogenesis, invasion, and metastasis. Suppression of STAT3 activation results in the induction of apoptosis in tumor cells, and accordingly its pharmacological modulation by tyrosine kinase inhibitors, antisense oligonucleotides, decoy nucleotides, dominant negative proteins, RNA interference and chemopreventive agents have been employed to suppress the proliferation of various human cancer cells in culture and tumorigenicity in vivo. However, the identification and development of novel drugs that can target deregulated STAT3 activation effectively remains an important scientific and clinical challenge. This review presents the evidence for critical roles of STAT3 in oncogenesis and discusses the potential for development of novel cancer therapies based on mechanistic understanding of STAT3 signaling cascade.

a b s t r a c t a r t i c l e i n f oHepatocellular carcinoma (HCC) is one of the most lethal malignancies, and is also the fourth most common cancer worldwide with around 700,000 new cases each year. Currently, first line chemotherapeutic drugs used for HCC include fluorouracil, cisplatin, doxorubicin, paclitaxel and mitomycin, but most of these are non-selective cytotoxic molecules with significant side effects. Sorafenib is the only approved targeted therapy by the U.S. Food and Drug Administration for HCC treatment, but patients suffer from various kinds of adverse effects, including hypertension. The signal-transducer-and-activator-of-transcription 3 (STAT3) protein, one of the members of STATs transcription factor family, has been implicated in signal transduction by different cytokines, growth factors and oncogenes. In normal cells, STAT3 activation is tightly controlled to prevent dysregulated gene transcription, whereas constitutively activated STAT3 plays an important role in tumorigenesis through the upregulation of genes involved in anti-apoptosis, proliferation and angiogenesis. Thus, pharmacologically safe and effective agents that can block STAT3 activation have the potential both for the prevention and treatment of HCC. In the present review, we discuss the possible role of STAT3 signaling cascade and its interacting partners in the initiation of HCC and also analyze the role of various STAT3 regulated genes in HCC progression, inflammation, survival, invasion and angiogenesis.

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Highlights d In vivo and in vitro genome-scale CD8 T cell CRISPR screen in immunotherapy contexts d Dhx37 knockout in CD8 T cells enhances adoptive transfer efficacy d Dhx37 modulates CD8 T cell activation, cytokine production, and cytotoxicity d DHX37 interacts with PDCD11 and influences NF-kB activity

DNA sequencing upstream of the Salmonella enterica serovar Typhi pilV and rci genes previously identified in the ca. 118-kb major pathogenicity island (X.-L. Zhang, C. Morris, and J. Hackett, Gene 202:139-146, 1997) identified a further 10 pil genes apparently forming a pil operon. The product of the pilS gene, prePilS protein (a putative type IVB structural prepilin) was purified, and an anti-prePilS antiserum was raised in mice. Mutants of serovar Typhi either lacking the whole pil operon or with an insertion mutation in the pilS gene were constructed, as was a strain in which the pilN to pilV genes were driven by the tac promoter. The pil Earlier, it was reported that the major pathogenicity island of Salmonella enterica serovar Typhi, which is ca. 118 kb in size (11), contained pilV and rci genes, which were cloned and sequenced (22). The Rci gene product was shown to be a site-specific recombinase, active to invert DNA in the C-terminal region of the pilV gene, so that two PilV proteins could be synthesized. Comparisons with database sequences indicated that the two possible pilV genes might code for pilus-tip adhesins, as the serovar Typhi PilV sequence was similar to that of PilV proteins encoded by the Escherichia coli R64 plasmid. In R64-bearing strains, different PilV proteins, borne on type IV pili, select various recipients in liquid mating (the R64-bearing cell is the donor) (10). Both serovar Typhi PilV proteins were seen when the two pilV genes were transcribed from the T7 promoter. The discovery of the serovar Typhi pilV and rci genes in the ca. 118-kb pathogenicity island (henceforth in this work termed the large pathogenicity island) suggested that serovar Typhi might synthesize thin pili belonging to the type IV pilin family (9). As type IV pili, encoded in a Vibrio cholerae pathogenicity island (7, 8) are used by V. cholerae as mediators of adhesion to human cells (13, 18), it was of interest to ask (i) if serovar Typhi also synthesizes type IV pili and (ii) if such pili are important in adherence to or invasion of human intestinal cells. These topics are the subject of this paper. MATERIALS AND METHODSMaterials. All reagents were of molecular biology grade. Enzymes active on DNA were obtained from either GibcoBRL or Boehringer Mannheim and were used as directed by the suppliers. 5-Bromo-4-chloro-3-indolyl-␤-D-galactopyranoside and isopropyl-␤-D-thiogalactopyranoside were purchased from Amersham. Anti-mouse immunoglobulin G (from sheep), conjugated with horseradish peroxidase, was from Amersham. Phosphatase-labeled goat anti-mouse immunoglobulin G (heavy and light chains) was purchased from KPL Laboratories. p-Nitrophenyl phosphate tablets were from Sigma. Bio-Rad was the supplier of polyvinylidene difluoride membrane. Freund's adjuvant was from GibcoBRL.Strains and vectors. Serovar Typhi J341 (Ty2 Vi Ϫ ) (22) was the source of DNA for a cosmid bank (partially Sau3AI-cut DNA in BamHI-cut pHC79), which was probed with 32 P-labeled total DNA (including the virulence plasmid pSLT) of (wild-type,...

Oleanolic acid (OA, 3β-hydroxyolean-12-en-28-oic acid) is a ubiquitous pentacyclic multifunctional triterpenoid, widely found in several dietary and medicinal plants. Natural and synthetic OA derivatives can modulate multiple signaling pathways including nuclear factor-κB, AKT, signal transducer and activator of transcription 3, mammalian target of rapamycin, caspases, intercellular adhesion molecule 1, vascular endothelial growth factor, and poly (ADP-ribose) polymerase in a variety of tumor cells. Importantly, synthetic derivative of OA, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), and its C-28 methyl ester (CDDO-Me) and C28 imidazole (CDDO-Im) have demonstrated potent antiangiogenic and antitumor activities in rodent cancer models. These agents are presently under evaluation in phase I studies in cancer patients. This review summarizes the diverse molecular targets of OA and its derivatives and also provides clear evidence on their promising potential in preclinical and clinical situations.

Background: Constitutive activation of STAT3 is associated with the progression of hepatocellular carcinoma (HCC), and abrogation of STAT3 signaling is a potential target for HCC treatment. Results: A novel azaspirane modulates the JAK-STAT pathway in HCC. Conclusion:The lead compound induces apoptosis by down-regulating STAT3 signaling. Significance: This investigation reports a novel inhibitor of the JAK-STAT pathway with the potential to target various cancers.