Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion.

LKB1 is a tumor susceptibility gene for the Peutz-Jeghers cancer syndrome and is a target for mutational inactivation in sporadic human malignancies. LKB1 encodes a serine/threonine kinase that has critical roles in cell growth, polarity and metabolism. A novel and important function of LKB1 is its ability to regulate the phosphorylation of CREB-regulated transcription co-activators (CRTCs) whose aberrant activation is linked with oncogenic activities. However, the roles and mechanisms of LKB1 and CRTC in the pathogenesis of esophageal cancer have not been previously investigated. In this study, we observed altered LKB1-CRTC signaling in a subset of human esophageal cancer cell lines and patient samples. LKB1 negatively regulates esophageal cancer cell migration and invasion in vitro. Mechanistically, we determined that CRTC signaling becomes activated because of LKB1 loss, which results in the transcriptional activation of specific downstream targets including LYPD3, a critical mediator for LKB1 loss-of-function. Our data indicate that de-regulated LKB1-CRTC signaling might represent a crucial mechanism for esophageal cancer progression.

Circadian variation in circulating pyrogen: possible role in resistance to infection.

In the rat, body temperature (bt) is highest, and plasma iron (Fe) and zinc (Zn) concentrations are lowest at night while the rat is most active; the inverse is true during the day. Based on data implicating endogenous pyrogen (EP) as a mediator of the rise in body temperature and fall in plasma trace metal levels during infection we hypothesized that the circadian rise in body temperature and fall in plasma Fe and Zn levels may be attributed to a cyclic release of EP. To test this hypothesis: (1) Rats were injected ip with an antipyretic dose of sodium salicylate (300 mg/kg). The result was a reduction (P less than 0.05) in bt at night. (2) Rats were injected during the day with 1 ml each of plasma collected from rats during the night. As a control, rat plasma collected during the day was injected at this same time point. A rise (P less than 0.05) in bt was observed only in animals who had received plasma collected at night. These results support the hypothesis that a pyrogen, perhaps EP, is present in the plasma of rats at night. The release of EP during periods of greatest activity may have an adaptive role since rats are more likely to come into contact with pathogens during these times. If EP were released during periods of activity, the likelihood of severe infection occurring would be diminished. To test this hypothesis, two groups of rats were injected with Salmonella typhimurium, one group at midnight (A) and one group at noon (B). The mortality rate was 25% in group A and 60% in group B (P less than 0.025). These data support the hypothesis that the immune/host defense of rats to S. typhimurium is more effective at night, possibly due to an increased level of circulating pyrogen.