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Review
. 2010 Jan;31(1):37-49.
doi: 10.1093/carcin/bgp272. Epub 2009 Dec 2.

Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways

Aaron J Schetter  1 , Niels H H Heegaard, Curtis C Harris
Affiliations
Review

Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways

Aaron J Schetter et al. Carcinogenesis. 2010 Jan.

Abstract

Chronic inflammation and infection are major causes of cancer. There are continued improvements to our understanding of the molecular connections between inflammation and cancer. Key mediators of inflammation-induced cancer include nuclear factor kappa B, reactive oxygen and nitrogen species, inflammatory cytokines, prostaglandins and specific microRNAs. The collective activity of these mediators is largely responsible for either a pro-tumorigenic or anti-tumorigenic inflammatory response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. As our understanding grows, inflammatory mediators will provide opportunities to develop novel diagnostic and therapeutic strategies. In this review, we provide a general overview of the connection between inflammation, microRNAs and cancer and highlight how our improved understanding of these connections may provide novel preventive, diagnostic and therapeutic strategies to reduce the health burden of cancer.

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Figures

Fig. 1.
Fig. 1.
Chronic inflammation alters the cellular levels of inflammatory mediators, including COX-2, RONS and inflammatory cytokines and activates proto-oncogenes. Depending on the collective functions and balance of inflammatory mediators, an inflammatory response may be either pro- or anti-tumorigenic.
Fig. 2.
Fig. 2.
Inflammation-induced NO• production can be pro- or anti-tumorigenic, depending on the functional status of the tumor suppressor p53. Under conditions with functional p53, NO• promotes the stabilization of p53 and p53 then acts in a negative feedback loop to reduce NOS2 and NO•. Elevated p53 levels then lead to an overall tumor-suppressive effect. In the absence of functional p53, an inflammatory stimulus can lead to the over-production of NO•. Without p53, NO• levels remain high leading to pro-tumorigenic conditions. This includes activating proto-oncogenes, inactivating tumor suppressor genes, increased cell proliferation and increased angiogenesis.
Fig. 3.
Fig. 3.
MicroRNAs are inflammatory mediators. (A) MicroRNA expression levels are altered in a variety of inflammatory conditions. Underlined microRNAs are highlighted in panel (B). (B) The expression of oncogenic microRNAs is induced by inflammatory cytokines. These microRNAs can then _target inflammatory mediators, tumor suppressor genes or oncogenes to have a role in inflammation-induced carcinogenesis.
Fig. 4.
Fig. 4.
The combination of multiple, validated biomarkers may improve predictions of clinical outcomes. In this example, microRNA expression biomarkers and inflammatory gene biomarkers are combined to improve associations with prognosis. Theoretical Kaplan–Meier plots are shown with time on the X axis and survival probability on the Y axis. Each biomarker misclassifies a different subset of patients and combining these biomarkers provides a more accurate prediction. This proof of principle of this strategy has recently been shown in colon cancer patients to improve predictions of cancer-specific mortality by combining inflammatory gene and microRNA biomarkers (123).
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