Project description:Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine neoplasias of neural crest origin. They can be part of several syndromes, and their mRNA profile is dependent on genetic background, but questions related to clinical behavior or even main location remain unanswered. MicroRNAs are key modulators of target genes through translational repression, mRNA degradation, or both, and therefore they could resolve some of these issues. To determine the role microRNAs play in tumorigenesis and progression of PCC/PGL, as well as to identify microRNA biomarkers specifically related to different PCC/PGL genetic classes known so far, we characterized microRNA profiles in a large series of frozen tumors with germline mutations in SDHD, SDHB, VHL, RET, NF1, and TMEM127 genes through microarray analysis. We identified microRNA signatures specific to, as well as common among, the genetic classes of PCC/PGLs, and the best candidate microRNAs (miR-122, miR-126*, miR-129*, miR-133b, miR-137, miR-183, miR-210, miR-382, miR-488, miR-885-5p, and miR-96) were validated in an independent series of formalin-fixed paraffin-embedded PCC/PGL samples by qRT-PCR. MicroRNA-137, -96/183, and -143/145 expression in PCC/PGLs correlated inversely with the differentiation status of tumor cells. MicroRNA-210, -382, and -380 could modulate pseudohypoxic cellular response in VHL-deficient PCC/PGL. MicroRNA-193b, -365, and -424 were commonly downregulated among all genetic classes, suggesting their involvement in cell cycle control and differentiation. Herein, we demonstrate that PCC/PGLs have different microRNA profiles according to the underlying primary mutation, suggesting they could be used as specific biomarkers and add information on the etiology of these tumors.
Project description:Aim: To investigate the differentially expressed circular RNAs (circRNAs) and their potential functions in pheochromocytomas and paragangliomas (PCC/PGLs). Materials & Methods: We analyzed the expression levels of circRNAs through RNA sequencing in tumor and adjacent normal tissues from 7 PCC/PGL patients. Real-time qPCR was conducted to verify the key candidates identified in the sequencing data. GO and KEGG Pathway analyses were performed to predict the functions of these circRNAs. The circRNA-miRNA-mRNA coding-noncoding gene co-expression (CNC) networks were mapped to show the potential binding relationship between circRNAs and their targets in PCC/PGLs. Results: A total of 367 circRNAs were shown to have differential expression between tumor and normal samples. The top 3 histone methylation-related circRNAs (hsa_circ_0000567, hsa_circ_0002897, hsa_circ_0004473) and their target miRNAs were identified and validated. The top 5 mRNAs, 88 miRNAs, and 132 circRNAs related to the pathogenesis were utilized to map the CNC network, and we observed that the interactions of these candidates with their target miRNAs regulated the procedure of histone-methylation, and further controlled the pathogenesis of PCC/PGLs. Conclusions: Our study is the first to provide the whole profile of differentially expressed circRNAs in PCC/PGLs, and our data indicates that the altered circRNAs may control the pathogenesis of PCC/PGLs by regulating the histone-methylation processes and act as biomarkers.
Project description:Cyanobacterial blooms are an increasing source of environmental toxins that affect both human and animals. After ingestion of cyanobacteria, such as Geitlerinema sp., toxins and lipopolysaccharide (LPS) from this organism induce fever, gastrointestinal illness, and even death. However, little is known regarding the effects of cyanobacterial LPS on human monocytes after exposure to LPS upon ingestion. Based on our previous data using Geitlerinema sp. LPS (which was previously named Oscillatoria sp., a genus belonging to the same order as Geitlerinema), we hypothesized that Geitlerinema sp. LPS would activate human monocytes to proliferate, phagocytose particles, and produce cytokines that are critical for promoting proinflammatory responses in the gut. Our data demonstrate that Geitlerinema sp. LPS induced monocyte proliferation and TNF-α, IL-1, and IL-6 production at high concentrations. In contrast, Geitlerinema sp. LPS is equally capable of inducing monocyte-mediated phagocytosis of FITC-latex beads when compared with Escherichia coli LPS, which was used as a positive control for our experiments. In order to understand the mechanism responsible for the difference in efficacy between Geitlerinema sp. LPS and E. coli LPS, we performed biochemical analysis and identified that Geitlerinema sp. LPS was composed of significantly different sugars and fatty acid side chains in comparison to E. coli LPS. The lipid A portion of Geitlerinema sp. LPS contained longer fatty acid side chains, such as C15:0, C16:0, and C18:0, instead of C12:0 found in E. coli LPS which may explain the decreased efficacy and toxicity of Geitlerinema sp. LPS in comparison to E. coli LPS.