Comprehensive analysis of ceRNA networks in HPV16- and HPV18-mediated cervical cancers reveals XIST as a pivotal competing endogenous RNA.

Cervical cancer (CC) is one of the most common cancers in women worldwide, being closely related to high-risk human papillomavirus (HR-HPVs). After a particular HR-HPV infects a cervical cell, transcriptional changes in the host cell are expected, including the regulation of lncRNAs, miRNAs, and mRNAs. Such transcripts may work independently or integrated in complex molecular networks - as in competing endogenous RNA (ceRNA) networks. In our research, we gathered transcriptome data from samples of HPV16/HPV18 cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), from The Cancer Genome Atlas (TCGA) project. Using GDCRNATools, we identified ceRNA networks that differentiate HPV16- from HPV18-mediated CESC. For HPV16-CESC, three lncRNA-mRNA co-expressed pairs were reported, all led by the X-inactive specific transcript (XIST): XIST | DLG5, XIST | LGR4, and XIST | ZNF81. The XIST | LGR4 and XIST | ZNF81 pairs shared 11 miRNAs, suggesting an increased impact on their final biological effect. XIST also stood out as an important lncRNA in HPV18-CESC, leading 35 of the 42 co-expressed pairs. Some mRNAs, such as ADAM9 and SLC38A2, emerged as important players in the ceRNA regulatory networks due to sharing a considerable amount of miRNAs with XIST. Furthermore, some XIST-associated axes, namely XIST | miR-23a-3p | LGR4 and XIST | miR-30b-5p or miR-30c-5p or miR-30e-5p I ADAM9, had a significant impact on the overall survival of HPV16- and HPV18-CESC patients, respectively. Together, these data suggest that XIST has an important role in HPV-mediated tumorigenesis, which may implicate different molecular signatures between HPV16 and HPV18-associated tumors.

Gene expression is associated with virulence in murine macrophages infected with Leptospira spp.

Leptospira genus contains species that affect human health with varying degrees of pathogenicity. In this context, we aimed to evaluate the differences in the modulation of host gene expression by strains of Leptospira varying in virulence. Our data showed a high number of differentially expressed transcripts in murine macrophages following 6h of infection. Leptospira infection modulated a set of genes independently of their degree of virulence. However, pathway analysis indicated that Apoptosis, ATM Signaling, and Cell Cycle: G2/M DNA Damage Checkpoint Regulation were exclusively regulated following infection with the virulent strain. Taken together, results demonstrated that species and virulence play a role during host response to Leptospira spp in murine macrophages, which could contribute to understanding the pathogenesis of leptospirosis.

Induction of miR 21 impairs the anti-Leishmania response through inhibition of IL-12 in canine splenic leukocytes.

Visceral Leishmaniasis is a chronic zoonosis and, if left untreated, can be fatal. Infected dogs have decreased cellular immunity (Th1) and develop a potent humoral response (Th2), which is not effective for elimination of the protozoan. Immune response can be modulated by microRNAs (miRNAs), however, characterization of miRNAs and their possible regulatory role in the spleen of infected dogs have not been done. We evaluated miRNA expression in splenic leukocytes (SL) from dogs naturally infected with Leishmania infantum and developing leishmaniasis (CanL; n = 8) compared to healthy dogs (n = 4). Microarray analysis showed increased expression of miR 21, miR 148a, miR 7 and miR 615, and downregulation of miR 150, miR 125a and miR 125b. Real-time PCR validated the differential expression of miR 21, miR 148a and miR 615. Further, decrease of miR 21 in SL, by means of transfection with a miR 21 inhibitor, increased the IL-12 cytokine and the T-bet/GATA-3 ratio, and decreased parasite load on SL of dogs with CanL. Taken together, these findings suggest that L. infantum infection alters splenic expression of miRNAs and that miR 21 interferes in the cellular immune response of L. infantum-infected dogs, placing this miRNA as a possible therapeutic target in CanL.

Relationship of peripheral blood mononuclear cells miRNA expression and parasitic load in canine visceral leishmaniasis.

Visceral leishmaniasis (VL) in humans is a chronic and often fatal disease if left untreated. Dogs appear to be the main reservoir host for L. infantum infection, however, in many regions other canids such as jackals, foxes, wolves and other mammals, such as hares or black rats, have been implicated as wild reservoirs. Most dogs cannot form an effective immune response against this infection, and this could be modulated by small non-coding RNAs, called microRNAs, responsible for post-transcriptional control of gene expression. Here, we evaluated the expression of miRNAs in peripheral blood mononuclear cells (PBMC) of symptomatic dogs naturally infected with Leishmania (L.) infantum (n = 10) and compared to those of healthy dogs (n = 5). Microarray analysis revealed that miR-21, miR-424, miR-194 and miR-451 had a 3-fold increase in expression, miR-192, miR-503, and miR-371 had a 2-fold increase in expression, whereas a 2-fold reduction in expression was observed for miR-150 and miR-574. Real-time PCR validated the differential expression of miR-21, miR-150, miR-451, miR-192, miR-194, and miR-371. Parasite load of PBMC was measured by real-time PCR and correlated to the differentially expressed miRNAs, showing a strong positive correlation with expression of miR-194, a regular positive correlation with miR-371 expression, and a moderate negative correlation with miR-150 expression in PBMC. These findings suggest that Leishmania infection interferes with miRNAs expression in PBMC, and their correlation with parasite load may help in the identification of therapeutic targets in Canine Visceral Leishmaniasis (CVL).

Data on differentially expressed miRNAs in dogs infected with Leishmania infantum.

This paper contains data on differentially expressed miRNAs in peripheral blood mononuclear cells (PBMC) of dogs naturally infected by Leishmania (L.) infantum compared to healthy dogs. In recent years, studies with miRNAs have shown that these molecules play a critical role in the regulation and function of immune response.Differentially expressed miRNAs were identified by microarray, validated by real time PCR and compared with parasite load in the dogs. Targets and pathways were analyzed using the Ingenuity Pathway Analysis program.

Characterization of the microtranscriptome of macrophages infected with virulent, attenuated and saprophyte strains of Leptospira spp.

Leptospirosis is a bacterial zoonosis, caused by Leptospira spp., that leads to significant morbidity and mortality worldwide. Despite considerable advances, much is yet to be discovered about disease pathogenicity. The influence of epigenetic mechanisms, particularly RNA-mediated post-transcriptional regulation of host immune response has been described following a variety of bacterial infections. The current study examined the microtranscriptome of macrophages J774A.1 following an 8h infection with virulent, attenuated and saprophyte strains of Leptospira. Microarray analysis revealed that 29 miRNAs were misregulated following leptospiral infection compared to control macrophages in a strain and virulence-specific manner. Pathway analysis for targets of these differentially expressed miRNAs suggests that several processes involved in immune response could be regulated by miRNAs. Our data provides the first evidence that host miRNAs are regulated by Leptospira infection in macrophages. A number of the identified miRNA targets participate in key immune response processes. We suggest that post-transcriptional regulation by miRNAs may play a role in host response to infection in leptospirosis.

Transcriptome datasets of macrophages infected with different strains of Leptospira spp.

The datasets reported herein provide information about microarray experiment of macrophage cell line J774A.1 infected with three different strains of Leptospira spp. Transcriptomic profiles were generated using Affymetrix® Mouse Gene 2.1 ST Array Strip. Data was normalized and statically process, p-value < 0.01, FDR < 0.05 and log2 fold change (± 2). The microarray raw data are available in Gene Expression Omnibus (GEO) under accession number GSE105141.