Colon adenocarcinoma is a major cause of cancer mortality worldwide.¹ Colorectal cancer is the third most common and second leading cause of cancer death in the United States.² Even though 5-year mortality rates have modestly declined over the last 3 decades,³ there is still a need to identify new prognostic biomarkers and therapeutic targets for this disease. Currently, chemotherapy has significant therapeutic value, but surgery is the only curative form of treatment.⁴

G ₁ /S and G ₂ /M cell cycle checkpoints maintain genomic stability in eukaryotes in response to genotoxic stress. We report here both genetic and functional evidence of a Gadd45-mediated G ₂ /M checkpoint in human and murine cells. Increased expression of Gadd45 via microinjection of an expression vector into primary human fibroblasts arrests the cells at the G ₂ /M boundary with a phenotype of MPM2 immunopositivity, 4 n DNA content and, in 15% of the cells, centrosome separation. The Gadd45-mediated G ₂ /M arrest depends on wild-type p53, because no arrest was observed either in p53-null Li–Fraumeni fibroblasts or in normal fibroblasts coexpressed with p53 mutants. Increased expression of cyclin B1 and Cdc25C inhibited the Gadd45-mediated G ₂ /M arrest in human fibroblasts, indicating that the mechanism of Gadd45-mediated G ₂ /M checkpoint is at least in part through modulation of the activity of the G ₂ -specific kinase, cyclin B1/p34 ^cdc2 . Genetic and physiological evidence of a Gadd45-mediated G ₂ /M checkpoint was obtained by using GADD45 -deficient human or murine cells. Human cells with endogenous Gadd45 expression reduced by antisense GADD45 expression have an impaired G ₂ /M checkpoint after exposure to either ultraviolet radiation or methyl methanesulfonate but are still able to undergo G ₂ arrest after ionizing radiation. Lymphocytes from gadd45 -knockout mice ( gadd45 −/−) also retained a G ₂ /M checkpoint initiated by ionizing radiation and failed to arrest at G ₂ /M after exposure to ultraviolet radiation. Therefore, the mammalian genome is protected by a multiplicity of G ₂ /M checkpoints in response to specific types of DNA damage.

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.