LINC01980 induced by TGF-beta promotes hepatocellular carcinoma metastasis via miR-376b-5p/E2F5 axis.

Hepatocellular carcinoma (HCC) is one of the most aggressive human malignancies worldwide. However, the molecular mechanism of HCC metastasis is largely unknown. Long non-coding RNA (lncRNA) plays a key role in gene regulation, and dysregulation of lncRNA is critical to cancer metastasis. LINC01980 has been reported in ESCC recently, but the mechanism underlying its function in HCC is still unknown. In this study, we found that LINC01980 was upregulated and associated with notably poor overall survival in HCC patients. Functionally, LINC01980 played a carcinogenic role and promoted HCC metastasis. Mechanically, LINC01980 enhanced the E2F5 expression via competitively binding miR-376b-5p, thereby inducing epithelial-mesenchymal transition and promoting HCC cells migration and invasion. In addition, LINC01980-mediated HCC cells metastasis was dependent on E2F5. What's more, TGF-ß activated LINC01980 transcription through the canonical TGF-ß/SMAD signaling pathway in HCC. In conclusion, LINC01980, activated by the canonical TGF-ß/SMAD pathway, promoted HCC metastasis via miR-376b-5p/E2F5 axis. Therefore, LINC01980 might be a potential prognostic biomarker and therapeutic target of HCC.

Ring finger protein 12 activates AKT signalling to promote the progression of liver cancer by interacting with EGFR.

Liver cancer is one of the most common solid tumours, and ranks as the third leading cause of cancer-associated mortality around the world. This study has linked RNF12 to the pathogenesis of liver cancer. Based on the analysis of patient samples and database data, high RNF12 expression was found in liver cancer, in correlation with worse clinicopathological features and a poor prognosis. Meantime, RNF12 could promote the progression of liver cancer in vitro and in vivo. Mechanistically, RNF12 could interact with EGFR and decrease the internalization of EGFR to activate EGF/EGFR signalling. In addition, PI3K-AKT signalling takes part in the regulation of liver cancer cell proliferation and migration of RNF12. And AKT inhibitor MK2206 could reverse RNF12-mediated cellular proliferation and migration in liver cancer. The possibility of the physical interaction between RNF12 and EGFR might lay a foundation to develop intervention strategies for liver cancer prevention and therapy.

Long noncoding RNA MAPKAPK5-AS1 promotes metastasis through regulation miR-376b-5p/ECT2 axis in hepatocellular carcinoma.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is one of the most common diseases threatening human health worldwide. However, the molecular mechanisms of HCC are still unclear. Here, we identified a differentially expressed lncRNA called MAPKAPK5-AS1(abbreviation: MK5-AS1) and elucidated its role and molecular mechanism in the development of HCC. METHODS: Real-time PCR (RT-PCR) was used to verify the expression of MK5-AS1 in hepatocarcinoma cell lines and tumor tissues of HCC patients. The biological functions of MK5-AS1 in HCC cells was assessed both in vitro and in vivo assays. The Lncbase, miRDB and TargetScan databases were used to predict the lncRNA-miRNA-mRNA interactions. RNA immunoprecipitation (RIP) and double luciferase reporter gene assays further verified the interactions. RESULTS: MK5-AS1 expression was significantly upregulated in HCC tissues and cell lines. Furthermore, high MK5-AS1 expression was positively associated with tumor progression and poor prognosis. In vitro and in vivo experiments confirmed that overexpressed MK5-AS1 promoted migration and invasion of HCC cells. Bioinformatics analysis based on Lncbase, miRDB and TargetScan databases showed MK5-AS1 competitively bound to miR-376b-5p that prevented epithelial cell transforming sequence 2 (ECT2) from miRNA-mediated degradation, thus facilitated HCC metastasis. CONCLUSION: Our results established a tumor promotive role of MK5-AS1 in HCC pathogenesis.

RHO GTPase family in hepatocellular carcinoma.

RHO GTPases are a subfamily of the RAS superfamily of proteins, which are highly conserved in eukaryotic species and have important biological functions, including actin cytoskeleton reorganization, cell proliferation, cell polarity, and vesicular transport. Recent studies indicate that RHO GTPases participate in the proliferation, migration, invasion and metastasis of cancer, playing an essential role in the tumorigenesis and progression of hepatocellular carcinoma (HCC). This review first introduces the classification, structure, regulators and functions of RHO GTPases, then dissects its role in HCC, especially in migration and metastasis. Finally, we summarize inhibitors targeting RHO GTPases and highlight the issues that should be addressed to improve the potency of these inhibitors.

Emerging roles of TRIM27 in cancer and other human diseases.

As a member of the TRIM protein family, TRIM27 is a RING-mediated E3 ubiquitin ligase that can mark other proteins for degradation. Its ubiquitination targets include PTEN, IκBα and p53, which allows it to regulate many signaling pathways to exert its functions under both physiological and pathological conditions, such as cell proliferation, differentiation and apoptosis. During the past decades, TRIM27 was reported to be involved in many diseases, including cancer, lupus nephritis, ischemia-reperfusion injury and Parkinson's disease. Although the research interest in TRIM27 is increasing, there are few reviews about the diverse roles of this protein. Here, we systematically review the roles of TRIM27 in cancer and other human diseases. Firstly, we introduce the biological functions of TRIM27. Next, we focus on the roles of TRIM27 in cancer, including ovarian cancer, breast cancer and lung cancer. At the same time, we also describe the roles of TRIM27 in other human diseases, such as lupus nephritis, ischemia-reperfusion injury and Parkinson's disease. Finally, we discuss the future directions of TRIM27 research, especially its potential roles in tumor immunity.

A Novel hepatocellular carcinoma specific hypoxic related signature for predicting prognosis and therapeutic responses.

Hypoxia is an important feature of the tumor microenvironment(TME) and is closely associated with cancer metastasis, immune evasion, and drug resistance. However, the precise role of hypoxia in hepatocellular carcinoma(HCC), as well as its influence on the TME, and drug sensitivity remains unclear. We found the excellent survival prediction value of Hypoxia_DEGs_Score model. In hypoxic HCC, somatic mutation, copy number variation, and DNA methylation were closely related to hypoxic changes and affected tumorigenesis, progression, metastasis, and drug resistance. In HCC, aggravated hypoxic stress was found to be accompanied by an immune exclusion phenotype and increased infiltration of immunosuppressive cells. In the validation cohort, patients with high Hypoxia_DEGs_Score were found to have worse immunotherapeutic outcomes and prognoses, and may benefit from drugs against cell cycle signaling pathways rather than those inhibiting the PI3K/mTOR pathway. Hypoxia_DEGs_Score has an excellent predictive capability of changes in the TME, the efficacy of immunotherapy, and the response of drugs. Therefore, Hypoxia_DEGs_Score can help develop personalized immunotherapy regimens and improve the prognosis of HCC patients.

Pan-cancer analysis combined with experimental validation revealed IL4I1 as an immunological and prognostic biomarker.

Interleukin-4-induced gene 1 (IL4I1) is a secreted l-phenylalanine oxidase that deaminates phenylalanine to phenylpyruvate, releasing H2O2 and NH3 in the process. IL4I1 is mainly secreted by inflammatory antigen presenting cells and is involved in the regulation of adaptive immune responses. Furthermore, it has been reported that IL4I1 is overexpressed in a variety of tumor tissues and affects tumor development. We explored the expression patterns, correlation with clinical traits and prognostic value of IL4I1 using public databases and microarray data from sample banks. Subsequently, we used the downloaded data to score tumor stromal cells and immune cell infiltration and analyzed the correlation between IL4I1 and immune cells or immune-related molecules in combination with TIMER2.0 and GEPIA databases. The analysis showed that IL4I1 was associated with the infiltration status of various immune cells. Finally, stable IL4I1-overexpressing hepatocellular carcinoma (HCC) cell lines were established to investigate the effect of IL4I1 on cell proliferation and motor capacity. All of these results suggest that IL4I1 is a potential biomarker and therapeutic target.

The Roles of FHL3 in Cancer.

The four and a half LIM domain protein 3, also named the LIM-protein FHL3, belongs to the LIM-only family. Based on the special structure of LIM-only proteins, FHL3 can perform significant functions in muscle proliferation and cardiovascular diseases by regulating cell growth and signal transduction. In recent years, there has been increasing evidence of a relation between FHLs and tumor biology, since FHL3 is often overexpressed or downregulated in different cancers. On the one hand, FHL3 can function as a tumor suppressor and influence the expression of downstream genes. On the other hand, FHL3 can also play a role as an oncoprotein in some cancers to promote tumor progression via phosphorylation. Thus, FHL3 is proposed to have a dual effect on cancer progression, reflecting its complex roles in cancer. This review focuses on the roles of FHL3 in cancer progression and discusses the interaction of FHL3 with other proteins and transcription factors. Finally, the clinical significance of FHL3 for the treatment of cancers is discussed.

The Roles of EphB2 in Cancer.

The erythropoietin-producing hepatocellular carcinoma (Eph) receptors and their Eph receptor-interacting (ephrin) ligands together constitute a vital cell communication system with diverse roles. Experimental evidence revealed Eph receptor bidirectional signaling with both tumor-promoting and tumor-suppressing activities in different cancer types and surrounding environment. Eph receptor B2 (EphB2), an important member of the Eph receptor family, has been proved to be aberrantly expressed in many cancer types, such as colorectal cancer, gastric cancer and hepatocellular carcinoma, resulting in tumor occurrence and progression. However, there are no reviews focusing on the dual roles of EphB2 in cancer. Thus, in this paper we systematically summarize and discuss the roles of EphB2 in cancer. Firstly, we review the main biological features and the related signaling regulatory mechanisms of EphB2, and then we summarize the roles of EphB2 in cancer through current studies. Finally, we put forward our viewpoint on the future prospects of cancer research focusing on EphB2, especially with regard to the effects of EphB2 on tumor immunity.

TDO2 Was Downregulated in Hepatocellular Carcinoma and Inhibited Cell Proliferation by Upregulating the Expression of p21 and p27.

BACKGROUND: Tryptophan-2,3-dioxygenase (TDO2) converts tryptophan into kynurenine in the initial limiting step of the kynurenine pathway. During the past decade, the overexpression of TDO2 has been found in various human tumors. However, the role of TDO2 in hepatocellular carcinoma is controversial, and we sought to clarify it in this study. METHODS: Western blot analysis and immunochemistry were used to detect the expression of TDO2 in human tissue specimens. The effect of TDO2 on cell proliferation in vitro was assessed using CCK8 and colony formation assays, and a xenograft mouse model was used to detect the effect of TDO2 on tumor growth in vivo. Flow cytometry was used to assess the cell cycle status. RESULTS: Low TDO2 expression was found in HCC and was associated with poor prognosis and adverse clinical outcomes. Conversely, TDO2 could restrain the proliferation of HCC cells in vivo and in vitro. Furthermore, TDO2 upregulated the expression of p21 and p27, inducing cell-cycle arrest. CONCLUSIONS: The loss of TDO2 expression in HCC was correlated with a poor prognosis and adverse clinical outcomes. At the same time, TDO2 could restrain the growth of HCC in vivo and in vitro. The results indicate that TDO2 is a potential biomarker and therapeutic target for HCC.

The Emerging Roles of circFOXO3 in Cancer.

Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs which are mainly formed by reverse splicing of precursor mRNAs. They are relatively stable and resistant to RNase R because of their covalently closed structure without 5' caps or 3' poly-adenylated tails. CircRNAs are widely expressed in eukaryotic cells and show tissue, timing, and disease specificity. Recent studies have found that circRNAs play an important role in many diseases. In particular, they affect the proliferation, invasion and prognosis of cancer by regulating gene expression. CircRNA Forkhead box O3 (circFOXO3) is a circRNA confirmed to be abnormally expressed in a variety of cancers, including prostate cancer, hepatocellular carcinoma, glioblastoma, bladder cancer, and breast cancer, etc. At present, the feature of circFOXO3 as a molecular sponge is widely studied to promote or inhibit the development of cancers. However, the diverse functions of circFOXO3 have not been fully understood. Hence, it is important to review the roles of circFOXO3 in cancers. This review has summarized and discussed the roles and molecular mechanism of circFOXO3 and its target genes in these cancers, which can help to enrich our understanding to the functions of circRNAs and carry out subsequent researches on circFOXO3.

The 14-3-3σ protein promotes HCC anoikis resistance by inhibiting EGFR degradation and thereby activating the EGFR-dependent ERK1/2 signaling pathway.

Resistance to anoikis, cell death due to matrix detachment, is acquired during tumor progression. The 14-3-3σ protein is implicated in the development of chemo- and radiation resistance, indicating a poor prognosis in multiple human cancers. However, its function in anoikis resistance and metastasis in hepatocellular carcinoma (HCC) is currently unknown. Methods: Protein expression levels of 14-3-3σ were measured in paired HCC and normal tissue samples using western blot and immunohistochemical (IHC) staining. Statistical analysis was performed to evaluate the clinical correlation between 14-3-3σ expression, clinicopathological features, and overall survival. Artificial modulation of 14-3-3σ (downregulation and overexpression) was performed to explore the role of 14-3-3σ in HCC anoikis resistance and tumor metastasis in vitro and in vivo. Association of 14-3-3σ with epidermal growth factor receptor (EGFR) was assayed by co-immunoprecipitation. Effects of ectopic 14-3-3σ expression or knockdown on EGFR signaling, ligand-induced EGFR degradation and ubiquitination were examined using immunoblotting and co-immunoprecipitation, immunofluorescence staining, and flow cytometry analysis. The levels of EGFR ubiquitination, the interaction between EGFR and 14-3-3σ, and the association of EGFR with c-Cbl after EGF stimulation, in 14-3-3σ overexpressing or knockdown cells were examined to elucidate the mechanism by which 14-3-3σ inhibits EGFR degradation. Using gain-of-function or loss-of-function strategies, we further investigated the role of the EGFR signaling pathway and its downstream target machinery in 14-3-3σ-mediated anoikis resistance of HCC cells. Results: We demonstrated that 14-3-3σ was upregulated in HCC tissues, whereby its overexpression was correlated with aggressive clinicopathological features and a poor prognosis. In vitro and in vivo experiments indicated that 14-3-3σ promoted anoikis resistance and metastasis of HCC cells. Mechanistically, we show that 14-3-3σ can interact with EGFR and significantly inhibit EGF-induced degradation of EGFR, stabilizing the activated receptor, and therefore prolong the activation of EGFR signaling. We demonstrated that 14-3-3σ downregulated ligand-induced EGFR degradation by inhibiting EGFR-c-Cbl association and subsequent c-Cbl-mediated EGFR ubiquitination. We further verified that activation of the ERK1/2 pathway was responsible for 14-3-3σ-mediated anoikis resistance of HCC cells. Moreover, EGFR inactivation could reverse the 14-3-3σ-mediated effects on ERK1/2 phosphorylation and anoikis resistance. Expression of 14-3-3σ and EGFR were found to be positively correlated in human HCC tissues. Conclusions: Our results indicate that 14-3-3σ plays a pivotal role in the anoikis resistance and metastasis of HCC cells, presumably by inhibiting EGFR degradation and regulating the activation of the EGFR-dependent ERK1/2 pathway. To our best knowledge, this is the first report of the role of 14-3-3σ in the anoikis resistance of HCC cells, offering new research directions for the treatment of metastatic cancer by targeting 14-3-3σ.

LncRNA influence sequential steps of hepatocellular carcinoma metastasis.

As a class of new and crucial molecules involved in the regulation of biological function, long noncoding RNA (lncRNA) have obtained widespread attention in recent days. While it was thought that lncRNA would be redundant in the past, it is proved that lncRNA identify a class of molecular that regulate the homeostasis including hepatocellular carcinoma in the present. All kinds of lncRNA have been implicated in a various of diseases, particularly in tumorigenesis and metastasis. But the mechanisms how they act is still not entirely clear. Metastasis is a major factor affecting long-term survival in hepatocellular carcinoma (HCC) patients. Recently, growing numbers of experiments demonstrate that there is close connection between lncRNA and HCC metastasis. Here, we will briefly introduce a series of steps (primary tumor growth, angiogenesis, epithelial-to-mesenchymal transition, invasion, intravasation, survival in circulatory system, extravasation, dormancy and subsequent secondary tumor growth) of tumor metastasis, its classical but promising theories, the role of lncRNA in metastasis and the possible mechanisms involved. LncRNA, as potentially new and important tumor diagnostic and therapeutic molecules, has attracted much attention in recent years.

The Roles of TIF1γ in Cancer.

Transcriptional intermediary factor 1 γ (TIF1γ), also known as TRIM33, RFG7, PTC7, or Ectodermin, is an E3 ubiquitin-ligase family member with a ring-box-coiled-coil region. It can regulate TGF-ß/Smad signaling in two different ways in different cellular contexts. On one hand, TIF1γ can monoubiquitinate Smad4 to inhibit the formation of Smad2/3/4 nuclear complexes. On the other hand, TIF1γ can function as a cofactor of phosphorylated (p)-Smad2/3, competing with Smad4 to inhibit the formation of the Smad2/3/4 complex. In addition, TIF1γ has been reported to play a role in transcription elongation, cellular differentiation, embryonic development, and mitosis. As transforming growth factor-ß (TGF-ß) superfamily signaling plays an important role in the occurrence and development of cancer, and TIF1γ was reported to be involved in the regulation of TGF-ß superfamily signaling, studies on TIF1γ during the last decade have focused on its role in the development of cancer. However, TIF1γ can function either as a tumor suppressor or promoter in different cellular contexts, yet there are few reviews focusing on the roles of TIF1γ in cancer. Hence, in this paper we systematically review and discuss the roles of TIF1γ in cancer. Firstly, we review the biological features, the regulatory mechanisms and the related signaling pathways of TIF1γ. Next, we illustrate the roles of TIF1γ in different tumors. We then provide a tentative hypothesis that explains the dual roles of TIF1 γ in cancer. Finally, we provide our viewpoint regarding the future developments of cancer research focusing on TIF1γ, especially in relation to the effects of TIF1γ on tumoral immunity.

The Prognostic Value of the MiR-200 Family in Colorectal Cancer: A Meta-analysis with 1882 Patients.

Background: MicroRNAs are small non-coding RNAs containing 18-22 nucleotides which play a role in RNA silencing and post-transcriptional regulation of their target genes. The MiR-200 family comprises miR-141, miR-200a, miR-200b, miR-200c and miR-429. Increasing evidence indicates that miR-200 microRNAs play a role in cancer metastasis. For example, miR-200 microRNAs were reported to influence the prognosis in colorectal cancer patients by regulating the expression of genes related to the epithelial-mesenchymal transition6. Previous studies have shown that the high expression of miR-200 microRNAs has an impact on the overall survival and Relapse-free Survival of CRC patients. However, the study results were inconsistent. Results: Data from a total of 1882 patients from 9 studies was included in the meta-analysis. Poorer Relapse-free Survival (RFS) was observed in patients with high expression levels of miR-200 microRNAs (HR=1.13, 95% CI 1.04-1.23). Additionally, subgroup analysis of sample types revealed a significant association between higher expression of the miR-200 family in the plasma and poorer OS (HR=1.23, 95% CI 1.08-1.41) and RFS (HR=2.39, 95% CI 1.20-4.77), which indicates that the miR-200 family can be used as an easily detectable biomarker for evaluation of the prognosis of patients with colorectal cancer. Conclusions: High expression levels of miR-200 microRNAs were associated with poor clinical outcomes in colorectal cancer patients. The miR-200 family can therefore potentially serve as a prognostic biomarker. Further studies should be performed to verify the clinical utility of the miR-200 family in colorectal cancer.

Global Regulator PhoP is Necessary for Motility, Biofilm Formation, Exoenzyme Production and Virulence of Xanthomonas citri Subsp. citri on Citrus Plants.

Citrus canker caused by Xanthomonas citri subsp. citri is one of the most important bacterial diseases of citrus, impacting both plant growth and fruit quality. Identifying and elucidating the roles of genes associated with pathogenesis has aided our understanding of the molecular basis of citrus-bacteria interactions. However, the complex virulence mechanisms of X. citri subsp. citri are still not well understood. In this study, we characterized the role of PhoP in X. citri subsp. citri using a phoP deletion mutant, ΔphoP. Compared with wild-type strain XHG3, ΔphoP showed reduced motility, biofilm formation, as well as decreased production of cellulase, amylase, and polygalacturonase. In addition, the virulence of ΔphoP on citrus leaves was significantly decreased. To further understand the virulence mechanisms of X. citri subsp. citri, high-throughput RNA sequencing technology (RNA-Seq) was used to compare the transcriptomes of the wild-type and mutant strains. Analysis revealed 1017 differentially-expressed genes (DEGs), of which 614 were up-regulated and 403 were down-regulated in ΔphoP. Gene ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses suggested that the DEGs were enriched in flagellar assembly, two-component systems, histidine metabolism, bacterial chemotaxis, ABC transporters, and bacterial secretion systems. Our results showed that PhoP activates the expression of a large set of virulence genes, including 22 type III secretion system genes and 15 type III secretion system effector genes, as well as several genes involved in chemotaxis, and flagellar and histidine biosynthesis. Two-step reverse-transcription polymerase chain reaction analysis targeting 17 genes was used to validate the RNA-seq data, and confirmed that the expression of all 17 genes, except for that of virB1, decreased significantly. Our results suggest that PhoP interacts with a global signaling network to co-ordinate the expression of multiple virulence factors involved in modification and adaption to the host environment during infection.

FBXO22 promotes the development of hepatocellular carcinoma by regulating the ubiquitination and degradation of p21.

BACKGROUND: Deregulation of ubiquitin ligases is related to the malignant progression of human cancers. F-box only protein 22 (FBXO22), an F-box E3 ligase, is a member of the F-box protein family. However, the biological function of FBXO22 in HCC and the underlying molecular mechanisms are still unclear. In this study, we explored the role of FBXO22 in HCC and its mechanism of promoting tumor development. METHODS: We examined the expression of FBXO22 in normal liver cell lines, HCC cell lines, HCC tissue microarrays and fresh specimens. The correlation between FBXO22 and clinical features was analyzed in a retrospective study of 110 pairs of HCC tissue microarrays. Univariate and multivariate survival analyses were used to explore the prognostic value of FBXO22 in HCC. At the same time, the correlation between the FBXO22 and p21 was also studied in HCC samples. Knock-down and overexpression experiments, CHX and Mg132 intervention experiments, ubiquitination experiments, rescue experiments and nude mouse xenograft models were used to determine the potential mechanism by which FBXO22 promotes tumorigenesis in vitro and in vivo. RESULTS: The expression of FBXO22 in HCC tissues was significantly higher than in normal liver tissues. The overall survival rate and disease-free survival time of patients with high expression of FBXO22 were significantly shorter than those of patients with low expression of FBXO22. The high expression of FBXO22 in HCC tissues were significantly correlated with serum AFP (p = 0. 003, Pearson's chi-squared test), tumor size (p = 0. 019, Pearson's chi-squared test) and vascular invasion (p = 0. 031, Pearson's chi-squared test). Especially, Multivariate analysis showed that tumor size and the expression of FBXO22 were independent prognostic indicator of OS (95% CI: 1.077-5.157, P<0.05). Correlation analysis also showed that FBXO22 was negatively correlated with p21 in tissue microarrays (r = - 0.3788, P<0.001, Pearson correlation) and fresh specimens (r = - 0.4037, P<0.01, Pearson correlation). Moreover, both in vitro and in vivo experiments showed that knocking down FBXO22 expression could inhibit cell proliferation, while overexpression of FBXO22 promoted tumor formation. Furthermore, we identified that FBXO22 interacts with p21 by regulating protein stability and by influencing the ubiquitination process. A knockdown of FBXO22 decreased the ubiquitylation of p21, while overexpression enhanced it. CONCLUSIONS: This study uncovered a new mechanism by which FBXO22 functions as an oncogene in HCC pathogenesis and progression by mediating the ubiquitination and degradation of p21. It was also found that tumor size and the expression of FBXO22 were independent prognostic indicator of OS and the expression of FBXO22 and p21 was negatively correlated in clinical samples. Our findings present a new perspective for understanding the development of HCC, which may provide a new target for the treatment and management of this challenging cancer.

Integration Host Factor Is Essential for Biofilm Formation, Extracellular Enzyme, Zeamine Production, and Virulence in Dickeya zeae.

Dickeya zeae is a globally important pathogenic bacterium that infects many crops, including rice, maize, potato, and banana. Bacterial foot rot of rice caused by D. zeae is one of the most important bacterial diseases of rice in China and some Southeast Asian countries. To investigate the functions of integration host factor (IHF) in D. zeae, we generated knockout mutants of ihfA and ihfB. Phenotypic assays showed that both the ΔihfA and ΔihfB strains had greatly reduced mobility, biofilm formation, extracellular protease, and pectinase activities, and toxin production compared with the wild-type strain. In addition, the mutants did not inhibit the germination of rice seeds, failed to cause soft rot in potatoes and a hypersensitive response in tobacco, and were avirulent in rice. Quantitative reverse-transcription polymerase chain reaction analysis demonstrated that IHF positively regulates the expression of zmsA, hrpN/Y, pelA/B/C, pehX, celZ, prtG, fliC, and DGC (diguanylate cyclase). Electrophoretic mobility shift assays further confirmed that IhfA binds to the promoter region of the DGC gene and may alter the levels of a second bacterial messenger, c-di-GMP, to regulate the pathogenicity or other physiological functions of D. zeae. In summary, IHF is an important integrated regulator of pathogenicity in D. zeae.

The Clinicopathological and Prognostic Significance of IDO1 Expression in Human Solid Tumors: Evidence from a Systematic Review and Meta-Analysis.

BACKGROUND/AIMS: Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme catalyzing the initial and rate-limiting steps in the kynurenine pathway, which converts tryptophan into kynurenine. Upregulation of IDO1 decreases tryptophan levels and increases the accumulation of kynurenine and its metabolites. These metabolites can affect the proliferation of T cells. Increasing evidence has shown that IDO1 is highly expressed in various cancer types and associated with poor prognosis of cancer patients. However, the results were inconsistent. METHODS: We searched the Web of Science, PubMed, Embase and Cochrane library databases to identify studies evaluating the prognostic value of IDO1 in cancer patients. Pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by using fixed-effects/random-effects models. RESULTS: This systematic review and meta-analysis included 2706 patients from 24 articles. The results indicated a shorter overall survival in patients with high expression of IDO1 (hazard ratio [HR] = 2.03, 95% confidence interval [CI]: 1.56-2.63). Furthermore, disease-free survival was worse in patients with high expression of IDO1 (HR = 2.47, 95% CI: 1.46-4.20). Additionally, the pooled odds ratios (ORs) showed that increased IDO1 was significantly associated with tumor differentiation (OR = 1.81, 95% CI: 1.05-3.12), distant metastasis (OR = 1.45, 95% CI: 1.02-2.06), and poor clinical stage (OR = 1.89, 95% CI: 1.13-3.17). However, no significant correlation was observed of increased IDO1 expression with age, sex, lymph node metastasis, and tumor size. CONCLUSION: High expression of IDO1 is associated with poor clinical outcomes. IDO1 could serve as a biomarker of prognosis and a potential predictive factor of clinicopathology in various cancers. Further studies should be performed to verify the clinical utility of IDO1 in human solid tumors.

A New Insight into the Role of CART in Cocaine Reward: Involvement of CaMKII and Inhibitory G-Protein Coupled Receptor Signaling.

Cocaine- and amphetamine-regulated transcript (CART) peptides are neuropeptides that are expressed in brain regions associated with reward, such as the nucleus accumbens (NAc), and play a role in cocaine reward. Injection of CART into the NAc can inhibit the behavioral effects of cocaine, and injecting CART into the ventral tegmental area (VTA) reduces cocaine-seeking behavior. However, the exact mechanism of these effects is not clear. Recent research has demonstrated that Ca2+/calmodulin-dependent protein kinase II (CaMKII) and inhibitory G-protein coupled receptor (GPCR) signaling are involved in the mechanism of the effect of CART on cocaine reward. Hence, we review the role of CaMKII and inhibitory GPCR signaling in the effect of CART on cocaine reward and provide a new insight into the mechanism of that effect. In this article, we will first review the biological function of CART and discuss the role of CART in cocaine reward. Then, we will focus on the role of CaMKII and inhibitory GPCR signaling in cocaine reward. Furthermore, we will discuss how CaMKII and inhibitory GPCR signaling are involved in the mechanistic action of CART in cocaine reward. Finally, we will provide our opinions regarding the future directions of research on the role of CaMKII and inhibitory GPCR signaling in the effect of CART on cocaine reward.