Integrated analysis of gene expression signatures associated with colon cancer from three datasets.

PURPOSE: The present study aimed to elucidate the pathogenesis of colon cancer and identify genes associated with tumor development. METHODS: Three datasets, two (GSE74602 and GSE44861) from the Gene Expression Omnibus database and RNA-Seq colon cancer data from The Cancer Genome Atlas data portal, were downloaded. These three datasets were grouped using a meta-analysis approach, and differentially expressed genes (DEGs) were identified between colon tumor samples and adjacent normal samples. Functional enrichment analysis and regulatory factor predication were performed for significant genes. Additionally, small-molecule drugs associated with colon cancer were predicted, and a prognostic risk model was constructed. RESULTS: There were 251 overlapping DEGs (135 up- and 116 downregulated) between cancer samples and control samples in the three datasets. The DEGs were mainly involved in protein transport and apoptotic and neurotrophin signaling pathways. A total of 70 small-molecule drugs were predicated to be associated with colon cancer. Additionally, in the miRNA-target regulatory network, we found that SLC44A1 can be targeted by hsa-miR-183, hsa-miR-206, and hsa-miR-147, while KLF13 can be regulated by hsa-miR-182, hsa-miR-206, and hsa-miR-153. Moreover, the results of the prognostic risk model showed that four genes (VAMP1, P2RX5, CACNB1, and CRY2) could divide the samples into high and low risk groups. CONCLUSION: SLC44A1 and KLF13 may be involved in tumorigenesis and the metastasis of colon cancer by miRNA regulation. In addition, a four-gene (VAMP1, P2RX5, CACNB1, and CRY2) expression signature may have prognostic and predictive value in colon cancer.

Spatiotemporal and anatomical analyses of P2X receptor-mediated neuronal and glial processing of sensory signals in the rat dorsal horn.

Extracellularly released adenosine triphosphate (ATP) modulates sensory signaling in the spinal cord. We analyzed the spatiotemporal profiles of P2X receptor-mediated neuronal and glial processing of sensory signals and the distribution of P2X receptor subunits in the rat dorsal horn. Voltage imaging of spinal cord slices revealed that extracellularly applied ATP (5-500 µM), which was degraded to adenosine and acting on P1 receptors, inhibited depolarizing signals and that it also enhanced long-lasting slow depolarization, which was potentiated after ATP was washed out. This post-ATP rebound potentiation was mediated by P2X receptors and was more prominent in the deep than in the superficial layer. Patch clamp recording of neurons in the superficial layer revealed long-lasting enhancement of depolarization by ATP through P2X receptors during the slow repolarization phase at a single neuron level. This depolarization pattern was different from that in voltage imaging, which reflects both neuronal and glial activities. By immunohistochemistry, P2X(1) and P2X(3) subunits were detected in neuropils in the superficial layer. The P2X(5) subunit was found in neuronal somata. The P2X(6) subunit was widely expressed in neuropils in the whole gray matter except for the dorsal superficial layer. Astrocytes expressed the P2X(7) subunit. These findings indicate that extracellular ATP is degraded into adenosine and prevents overexcitation of the sensory system, and that ATP acts on pre- and partly on postsynaptic neuronal P2X receptors and enhances synaptic transmission, predominantly in the deep layer. Astrocytes are involved in sensitization of sensory network activity more importantly in the superficial than in the deep layer.

Sensing muscle ischemia: coincident detection of acid and ATP via interplay of two ion channels.

Ischemic pain--examples include the chest pain of a heart attack and the leg pain of a 30 s sprint--occurs when muscle gets too little oxygen for its metabolic need. Lactic acid cannot act alone to trigger ischemic pain because the pH change is so small. Here, we show that another compound released from ischemic muscle, adenosine tri-phosphate (ATP), works together with acid by increasing the pH sensitivity of acid-sensing ion channel number 3 (ASIC3), the molecule used by sensory neurons to detect lactic acidosis. Our data argue that ATP acts by binding to P2X receptors that form a molecular complex with ASICs; the receptor on sensory neurons appears to be P2X5, an electrically quiet ion channel. Coincident detection of acid and ATP should confer sensory selectivity for ischemia over other conditions of acidosis.