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Chronic inflammation is a major driving factor for the development of colitis-associated cancer (CAC). It is extensively acknowledged that patients who have long-standing inflammation bowel disease are at high risk for developing CAC. However, the metabolic alteration by which chronic intestinal inflammation promotes colorectal cancer is unclear. In the present study, we constructed dextran sulfate sodium (DSS)-induced colitis mouse model to uncover possible alterations in the metabolism indexes. Interestingly, after DSS diet administration, the expression of metabolism indexes and c-Myc increased. Moreover, in vitro, we treated cells with IL-6 to simulate inflammatory microenvironment and found that glucose uptake, lactate production, and lactate dehydrogenase activity increased dramatically, mirroring what were observed in vivo. In addition, the associative inhibition of STAT3 and c-Myc could significantly block the expression of metabolic enzymes. With the inhibition of STAT3/c-Myc signaling, meanwhile, the upregulation of both cell glucose uptake and lactate production by IL-6 pretreatment was reduced simultaneously. Thus, our study indicates that inflammation could induce metabolic disorder by promoting STAT3 signaling and c-Myc activity. Collectively, we find that metabolic disruptions triggered by inflammatory signaling are associated with tumorigenesis via the STAT3/c-Myc axis.

Background The authors previously reported that noncoding microRNA miR-219-5p is down-regulated in the spinal cord in a nociceptive state. The ventral tegmental area also plays critical roles in modulating nociception, although the underlying mechanism remains unknown. The authors hypothesized that miR-219-5p in the ventral tegmental area also may modulate nociception. Methods The authors studied the bidirectional regulatory role of ventral tegmental area miR-219-5p in a rat complete Freund’s adjuvant model of inflammatory nociception by measuring paw withdrawal latencies. Using molecular biology technologies, the authors measured the effects of astroglial coiled-coil and C2 domain containing 1A/nuclear factor κB cascade and dopamine neuron activity on the down-regulation of ventral tegmental area miR-219-5p–induced nociceptive responses. Results MiR-219-5p expression in the ventral tegmental area was reduced in rats with thermal hyperalgesia. Viral overexpression of ventral tegmental area miR-219-5p attenuated complete Freund’s adjuvant–induced nociception from 7 days after complete Freund’s adjuvant injection (paw withdrawal latencies: 6.09 ± 0.83 s vs. 3.96 ± 0.76 s; n = 6/group). Down-regulation of ventral tegmental area miR-219-5p in naïve rats was sufficient to induce thermal hyperalgesia from 7 days after lentivirus injection (paw withdrawal latencies: 7.09 ± 1.54 s vs. 11.75 ± 2.15 s; n = 8/group), which was accompanied by increased glial fibrillary acidic protein (fold change: 2.81 ± 0.38; n = 3/group) and reversed by intraventral tegmental area injection of the astroglial inhibitor fluorocitrate. The nociceptive responses induced by astroglial miR-219-5p down-regulation were inhibited by interfering with astroglial coiled-coil and C2 domain containing 1A/nuclear factor-κB signaling. Finally, pharmacologic inhibition of ventral tegmental area dopamine neurons alleviated this hyperalgesia. Conclusions Down-regulation of astroglial miR-219-5p in ventral tegmental area induced nociceptive responses are mediated by astroglial coiled-coil and C2 domain containing 1A/nuclear factor-κB signaling and elevated dopamine neuron activity.

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