The Differential Expression of the Inflammasomes in Adipose Tissue and Colon Influences the Development of Colon Cancer in a Context of Obesity by Regulating Intestinal Inflammation.

Background: Inflammasomes maintain tissue homeostasis and their altered regulation in the colon, and the adipose tissue (AT) leads to chronic activation of inflammatory pathways promoting colon cancer (CC) development. We aimed to analyze the potential involvement of inflammasomes in obesity-associated CC.

Methods: Ninety-nine volunteers [61 with obesity (OB) and 38 normoponderal (NP)] further subclassified according to the approved protocol for the diagnosis of CC (58 without CC and 41 with CC) were included in the case-control study.

Results: CC (<0.01) and obesity (<0.01) were accompanied by increased mRNA levels of and in VAT. Contrarily, patients with CC exhibited a downregulation of and in their colon. Additionally, we revealed that the decreased (<0.05), (<0.01) and (<0.01) mRNA levels in the colon from obese rats significantly increase (<0.05) after caloric restriction. Adipocyte-conditioned media obtained from subjects with obesity reduced (<0.01) the mRNA of as well as molecules involved in maintaining the intestinal integrity ( and ) and the anti-inflammatory factors , and and in HT-29 cells. We also found that the knockdown of in HT-29 cells significantly upregulated (<0.05) the mRNA of and and inhibited (<0.05) the expression levels of . Finally, we showed that the incubation of HT-29 with influence (<0.05) the inflammasome expression profile as well as intestinal integrity-related genes and aberrant inflammation.

Conclusions: These findings provide evidence that the downregulated levels of and in the colon from patients with CC may be responsible for a reduced intestinal-barrier integrity, triggering local inflammation, which in turn acts on the dysfunctional AT in obesity, increasing the expression of different inflammasome components and flaring up a vicious cycle of uncontrollable inflammatory cascades that favours a pro-tumorigenic microenvironment.