Deleterious synergistic effects of distress and surgery on cancer metastasis: Abolishment through an integrated perioperative immune-stimulating stress-inflammatory-reducing intervention.

The perioperative period holds disproportionate impact on long-term cancer outcomes. Nevertheless, perioperative interventions to improve long-term cancer outcomes are not clinical routines, including perioperative stress-reducing or immune-stimulating approaches. Here, mimicking the clinical setting of pre-operative distress, followed by surgery, we examined the separate and combined effects of these events on the efficacy of pre-operative immune stimulation in rats and mice, and on post-operative resistance to tumor metastasis of the syngeneic mammary adenocarcinoma MADB106 in F344 rats and the CT26 colon carcinoma in Balb/C mice. The novel immune stimulating agents, GLA-SE or CpG-C (TLR-4 and TLR-9 agonists, respectively), were employed pre-operatively. Sixteen hours of pre-operative behavioral stressors (i) lowered CpG-C induced plasma IL-12 levels, and reduced resistance to MADB106 and CT-26 experimental metastases, and (ii) worsened the deleterious effects of laparotomy on metastasis in both tumor models. In rats, these effects of pre-operative stress were further studied and successfully abolished by the glucocorticoid receptor antagonist RU-486. Additionally, in vitro studies indicated the dampening effect of corticosterone on immune stimulation. Last, we tested a perioperative integrated intervention in the context of pre-operative stress and laparotomy, based on (i) antagonizing the impact of glucocorticoids before surgery, (ii) activating anti-metastatic immunity perioperatively, and (iii) blocking excessive operative and post-operative adrenergic and prostanoid responses. This integrated intervention successfully and completely abolished the deleterious effects of stress and of surgery on post-operative resistance to experimental metastasis. Such and similar integrated approaches can be studied clinically in cancer patients.

Multiple Copies of microRNA Binding Sites in Long 3'UTR Variants Regulate Axonal Translation.

Rapid responses to changes within subcellular compartments of highly polarized cells, such as neuron axons, depend on local translation and post-transcriptional regulation. The mechanism by which microRNAs (miRNAs) regulate this process is not fully understood. Here, using live cell imaging and RNA sequencing analysis, we demonstrated how miRNAs can differentially control hundreds of transcripts at the subcellular level. We demonstrated that the seed match length of the miRNA target-sequence regulates both mRNA stability and protein translation rates. While longer seed matches have an increased inhibitory effect, transcriptome analysis did not reveal differences in seed match length between axonal and somata mRNAs of motor neurons. However, mRNA variants with longer 3'UTR are enriched in axons and contain multiple repeats of specific miRNA target sequences. Finally, we demonstrated that the long 3'UTR mRNA variant of the motor protein Kif5b is enriched explicitly in motor neuron axons and contains multiple sequence repeats for binding miR-129-5p. This subsequently results in the differential post-transcriptional regulation of kif5b and its synthesis in axons. Thus, we suggest that the number of miRNA binding sites at the 3'UTR of the mRNA, rather than the miRNA seed match length, regulates the axonal transcriptome.