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Cancer Epidemiol Biomarkers Prev. 2018 Dec;27(12):1416-1423. doi: 10.1158/1055-9965.EPI-18-0121. Epub 2018 Oct 5.

Incremental Elevations in TNFα and IL6 in the Human Colon and Procancerous Changes in the Mucosal Transcriptome Accompany Adiposity.

Author information

1
Vitamins & Carcinogenesis Laboratory, The Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts.
2
Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts.
3
Genomics Core, Tufts University School of Medicine, Boston, Massachusetts.
4
Agricultural Research Service, The Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts.
5
Nutrition and Genomics Laboratory, The Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts.
6
School of Public Health and Health Sciences, University of Massachusetts, Amherst, Massachusetts.
7
Nutritional Epidemiology Laboratory, The Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts.
8
Vitamin K Laboratory, The Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts.
9
Vitamins & Carcinogenesis Laboratory, The Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts. joel.mason@tufts.edu.
10
Division of Gastroenterology, Tufts Medical Center, Boston, Massachusetts.
11
Division of Clinical Nutrition, Tufts Medical Center, Boston, Massachusetts.

Abstract

BACKGROUND:

Obesity, a risk factor for colorectal cancer, raises systemic levels of proinflammatory mediators. Whether increased levels also reside in the colons of obese individuals and are accompanied by procancerous alterations in the mucosal transcriptome is unknown.

METHODS:

Concentrations of TNFα, IL1β, and IL6 in blood and colonic mucosa of 16 lean and 26 obese individuals were examined. Differences in the mucosal transcriptome between the two groups were defined.

RESULTS:

Plasma IL6 and TNFα were 1.4- to 3-fold elevated in obese subjects [body mass index (BMI) ≥ 34 kg/m2] compared with the lean controls (P < 0.01). Among individuals with BMI ≥ 34 kg/m2 colonic concentrations of IL6 and TNFα were 2- to 3-fold greater than in lean subjects (P < 0.03). In a general linear model, adjusted for NSAID use, colonic IL6 (partial r = 0.41; P < 0.01) and TNFα (partial r = 0.41; P = 0.01) increased incrementally over the entire range of BMIs (18.1-45.7). Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with a reduction in colonic IL6 (β = -0.65, P < 0.02). RNA sequencing (NSAID users excluded) identified 182 genes expressed differentially between lean and obese subjects. The two gene networks most strongly linked to changes in expression included several differentially expressed genes known to regulate the procarcinogenic signaling pathways, NFκB and ERK 1/2, in a pattern consistent with upregulation of each in the obese subjects.

CONCLUSIONS:

Incremental increases in two major proinflammatory colonic cytokines are associated with increasing BMI, and in the obese state are accompanied by procancerous changes in the transcriptome.

IMPACT:

These observations delineate means by which an inflammatory milieu may contribute to obesity-promoted colon cancer.

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