Integrated miRNA and mRNA Expression Profiles Reveal Differentially Expressed miR-222a as an Antiviral Factor Against Duck Hepatitis A Virus Type 1 Infection

Duck hepatitis A virus 1 (DHAV-1) is a highly contagious etiological agent that causes acute hepatitis in young ducklings. MicroRNAs (miRNAs) play important regulatory roles in response to pathogens. However, the interplay between DHAV-1 infection and miRNAs remains ambiguous. We characterized and compared miRNA and mRNA expression profiles in duck embryo fibroblasts cells (DEFs) infected with DHAV-1. In total, 36 and 96 differentially expressed (DE) miRNAs, and 4110 and 2595 DE mRNAs, were identified at 12 and 24 h after infection. In particular, 126 and 275 miRNA–mRNA pairs with a negative correlation were chosen to construct an interaction network. Subsequently, we identified the functional annotation of DE mRNAs and target genes of DE miRNAs enriched in diverse Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, which may be important for virus resistance, cell proliferation, and metabolism. Moreover, upregulated miR-222a could negatively regulate DHAV-1 replication in DEFs and downregulate integrin subunit beta 3 (ITGB3) expression by targeting the 3′ untranslated region (3′UTR), indicating that miR-222a may modulate DHAV-1 replication via interaction with ITGB3. In conclusion, the results reveal changes of mRNAs and miRNAs during DHAV-1 infection and suggest miR-222a as an antiviral factor against DHAV-1.

Increased Expression of Integrin Subunit α3 is Correlated with Worse Recurrence-Free Survival in Thyroid Cancer

Objective: To investigate the potential effect of integrin subunit α3 (ITGA3) on thyroid cancer (THCA). Materials and Methods: Based on bioinformatics databases, the expression levels of ITGA3 were firstly analyzed, followed by evaluating the prognostic significance of ITGA3 in THCA patients. Cox regression analysis predicted the independent prognostic factors for THCA. Then, cBioportal and GSCA databases were applied to evaluate genetic alterations of ITGA3. Functional enrichment analysis was conducted using the R package. Finally, the upstream microRNAs of ITGA3 were determined. Results: ITGA3 gene and protein levels were higher in the THCA group than normal group (all P <0.05). And ITGA3 mRNA expression was significantly related to cancer stage and histological subtype (all P <0.01). Moreover, high expression of ITGA3 was associated with poor recurrence-free survival (RFS) of THCA patients in all subgroups (all P <0.01). Cox regression analysis presented that ITGA3 overexpression was an independent prognostic factor for worse RFS in THCA patients. Besides, significant relations were observed between ITGA3 and genetic alterations (FDR <0.01). Functional enrichment analysis indicated ECM-receptor interaction, and cell adhesion molecules were the shared regulatory pathways. We also found that ITGA3 might be the target gene of hsa-miR-3129, hsa-miR-181d, hsa-miR-181b, hsa-miR-199a, and hsa-miR-199b, which were all correlated with THCA patient prognosis. Conclusions: ITGA3 could be a reliable biomarker and promising therapeutic target for improving the diagnosis and clinical outcomes of THCA patients.

Coupling adipose tissue architecture and metabolism via cytoophidia

ABSTRACTTissue architecture determines its unique physiology and function. How these properties are intertwined has remained unclear. Here, we show that the metabolic enzyme CTP synthase (CTPS) form filamentous structures termed cytoophidia along the adipocyte cortex in Drosophila adipose tissue. Interestingly, loss of cytoophidia, whether due to reduced CTPS expression or a point mutation that specifically abrogates its polymerization ability, leads to downregulated Collagen-Integrin signaling, weakened adipocyte adhesion, and defective adipose architecture. Strikingly, CTPS specifically binds with Integrin subunit α2, which influences Integrin function and Collagen IV deposition. cytoophidia promote Collagen IV mRNA expression and thus its extracellular deposition to strengthen adipocyte adhesion. Remarkably, Collagen IV-Integrin signaling reciprocally regulates cytoophidium formation at a post-translational level. Together, we demonstrate that a positive feedback signaling loop containing both cytoophidia and Integrin adhesion complex couples tissue architecture and metabolism in the fly adipose.

TCN1 Deficiency Inhibits The Malignancy of Colorectal Cancer Cells By Regulating The ITGB4 Pathway

Background: This study aimed to investigate the biological function and regulatory mechanism of TCN1 in colorectal cancer (CRC). Methods: We studied the biological functions of TCN1 using gain-of-function and loss-of-function analysis in HCT116 cell lines, and examined the effects of TCN1 on the proliferation, apoptosis, and invasion of CRC cells and determined its potential molecular mechanisms using CRC lines and mouse xenotransplantation models. Tumor xenograft and tumor metastasis studies were performed to detect the tumorigenicity and metastasis of cells in vivo. Results: TCN1-knockdown attenuated CRC cell proliferation, invasion and promoted cell apoptosis. Overexpression of TCN1 yielded the opposite effects. In addition, TCN1-knockdown HCT116 cells failed to form metastatic foci in the peritoneum after intravenous injection. Molecular mechanism studies showed that TCN1 interacts with integrin subunit β4 (ITGB4) to positively regulate the expression of ITGB4. TCN1-knockdown promoted the degradation of ITGB4 and increased the instability of ITGB4 and filamin A (FLNA). Downregulation of ITGB4 at the protein level resulted in the disassociation of the ITGB4/PLEC complex, leading to cytoskeletal damage. Conclusion: TCN1 might exert oncogenic role in CRC via regulating the ITGB4 signaling pathway.

Omentin-1 Modulates Macrophage Function via Integrin Receptors αvβ3 and αvβ5 and Reverses Plaque Vulnerability in Animal Models of Atherosclerosis

Backgrounds: Omentin-1 is a novel cytokine that is primarily released by the epicardial adipose tissue. Molecular structure analysis revealed that it contained a fibrinogen-like domain. Clinical studies have demonstrated that the expression of omentin-1 is tightly associated with the development of cardiovascular diseases, but the receptor by which omentin-1 modulates macrophage function has not been identified yet.Objective: This study sought to investigate the effect of omentin-1 on already-established atherosclerosis (AS) lesions in both ApoE−/− and Ldlr−/− mice and further, study its underlying mechanisms.Methods and Results: We investigated the effect of omentin-1 on the plaque phenotype by implanting a minipump in ApoE−/− and Ldlr−/− mice. In vivo studies showed that the infusion of omentin-1 increased the collagen content and mitigated the formation of the necrotic core in both animal models. Immunohistochemistry and immunofluorescence analysis revealed that omentin-1 suppressed inflammatory cytokines expression, macrophage infiltration, and apoptosis within the plaque. An immunoprecipitation experiment and confocal microscopy analysis confirmed the binding of omentin-1 to the integrin receptors αvβ3 and αvβ5. The cell studies demonstrated that omentin-1 suppressed the apoptosis and inflammatory cytokines expression induced by the oxidized low-density lipoprotein in the macrophage. In addition, omentin-1 promoted the phosphorylation of the integrin-relevant signaling pathway as well as the Akt and AMPK in the macrophage. The addition of the inhibitor of the integrin receptor or interfering with the expression of the integrin subunit αv (ITGAV) both significantly abrogated the bioeffects induced by omentin-1. A flow cytometry analysis indicated that the antibodies against αvβ3 and αvβ5 had a competitive effect on the omentin-1 binding to the cell membrane.Conclusions: The administration of adipokine omentin-1 can inhibit the necrotic cores formation and pro-inflammatory cytokines expression within the AS lesion. The mechanisms may include the suppression of apoptosis and pro-inflammatory cytokines expression in the macrophage by binding to the integrin receptors αvβ3 and αvβ5.

Differential expression of ITGA6 in cancer of the vulva.

In these brief notes we document work using published microarray data (1, 2) to pioneer integrative transcriptome analysis comparing vulvar carcinoma to its tissue of origin, the vulva. We report the differential expression of integrin subunit alpha 6, encoded by ITGA6, in cancer of the vulva. ITGA6 may be of pertinence to understanding transformation and disease progression in vulvar cancer (3).

Polymorphism of the ITGAM gene (rs7193943) and bioelectric impedance analysis as potential predictors of cachexia in chronic heart failure

Cardiac cachexia (CC) is an unfavorable metabolic syndrome leading to exacerbation of chronic heart failure (CHF) and a higher risk of death. The main factor contributing to the development of cachexia is the ongoing inflammatory process mediated by genes (e.g. Integrin Subunit Alpha M—ITGAM). The study aimed to assess the relationship between a single nucleotide polymorphism (SNP) -323G > A of the ITGAM and the occurrence of nutritional disorders in patients with CHF. 157 CHF patients underwent clinical and nutritional screening. Body composition was evaluated by bioelectrical impedance analysis (BIA). Patients with cachexia were characterized by significantly lower weight, body mass index (BMI), lower fat mass (FM), albumin, and hemoglobin. Lower values of BIA parameters: capacitance of membrane (Cm), phase angle (PA), and impedance ratio (Z200/Z5) were noted in women. Those patients demonstrated significantly higher values of creatinine, c-reactive protein (CRP), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and pulmonary artery systolic pressure (PASP). A significantly higher risk of cachexia was reported in patients: aged ≥ 74 years (OR 3.55), with renal failure (OR 3.75), New York Heart Association classification (NYHA) III-IV (OR 2.83), with moderate or severe malnutrition according to the score of subjective global assessment (SGA) (OR 19.01) and AA genotype of ITGAM gene (OR 2.03). Determination of the -323G > A SNP in the ITGAM may prove to be a useful marker (after confirmation in further studies and appropriate validation) in the assessment of the risk of nutritional disorders in patients with CHF.

Relation among EGFL7, ITGB3, and KLF2 and their clinical implication in multiple myeloma patients: a prospective study

Objective We aimed to investigate the relationship among epidermal growth factor–like protein-7 (EGFL7), integrin subunit beta 3 (ITGB3), and Kruppel-like factor 2 (KLF2) expressions and their clinical implication in multiple myeloma (MM). Methods This prospective study enrolled 72 de novo symptomatic MM patients and 30 controls, and then collected their bone marrow plasma cell samples. Subsequently, the EGFL7, ITGB3, and KLF2 expressions were carried out by reverse transcription quantitative polymerase chain reaction. Results EGFL7, ITGB3, and KLF2 expressions were increased in MM patients compared to controls. Besides, EGFL7, ITGB3, and KLF2 inter-correlated with each other in MM patients but not in controls. In MM patients, EGFL7 and ITGB3 (but not KLF2) expressions were positively correlated with ISS stage, while ITGB3 and KLF2 (but not EGFL7) expressions were correlated with increased R-ISS stage. Interestingly, ITGB3 and KLF2 were decreased in induction-treatment complete remission (CR) MM patients compared to non-CR MM patients, while EGFL7 only showed a trend but without statistical significance. Furthermore, ITGB3 high expression was correlated with worse progression-free survival (PFS) and overall survival (OS), while EGFL7 and KLF2 high expressions only associated with pejorative PFS but not OS. Conclusion EGFL7, ITGB3, and KLF2 may serve as potential prognostic indicators in MM patients.