Tumor Promoting Inflammation Sept 14, 2017

Hallmarks of Cancer, 2011

Enabling Characteristics Hallmarks of Cancer, 2011

Inflammation and Genomic Instability Inflammatory cells and mediators can result in increased Genomic Instability by: Directly inducing DNA damage Affecting DNA Repair systems Altering Cell cycle checkpoints

Inflammation and Mismatch Repair Remember: Mutations or epigenetic silencing in MMR genes results in Microsatellite Instability 2 Effects: Increased non-specific mutation throughout genome Increased mutations in specific genes -Genes contain microsatellites -TGFβRII and IGF-2R (Growth regulation) -BAX (Apoptosis)

Inflammation down regulates MMR poteins Several mechanisms 1. HIF-1α down regulates MSH2/MSH6 -Inflammatory cytokines (TNF and IL-1β) induces production of HIF-1α -HIF-1α displaces c-Myc (transcription factor) from the promoters of the MSH2 and MSH6 genes

Inflammation down regulates MMR poteins Nitric Oxide up regulation of DNA Methyltransferase -Increase of DNA methyltransferase results in methylation of MLH1 promoter -Decreased levels of MLH1 protein found in patients with H. pylori positive patients

Inflammation down regulates MMR poteins Other mechanisms - MSI detected in patients with ulcerative colitis -Inactivation of MMR, mechanism unknown but may involve activated Neutrophils Ulcerated Normal

DNA Glycosylase Mechanism Encoded by the AAG gene

AP Endonuclease Encoded by the APE1 gene

Inflammation and Base Excision Repair -In ulcerative colitis patients, the APEI and AAG enzymes are significantly increased and also show microsatellite instability -Overexpression of these enzymes enhances microsatellite instability -ROS induces base excision repair enzymes -APE1 promoter contains a known binding sequence for NF-κB

– Repairs various DNA lesions caused by UV radiation and mutagenic chemicals hHR23B (RAD23B in yeast) -Functions to recruit other proteins to the site of DNA Damage

Inflammation and Nucleotide Excision Repair Nucleotide Excision Repair decreased by two methods 1. Cytokine IL-6 induces hypermethylation of hHR23B promoter reducing its expression 2. HIF-1α induces microRNA-373 which down regulates hHR23B What is a microRNA?

-Being used in research to target specific mRNAs for degradation. Therapeutic Value?

Inflammation and Chromosomal Instability Chromosomal Instability is the abnormal segregation of chromosomes resulting in aneuploidy Molecular mechanisms include mitotic checkpoints and regulators

p53 and Chromosome Instability -Tumor Suppressor

p53 and Chromosome Instability Several studies have shown that loss of p53 with another protein associated with chromosomal instability result in aneuploidy Mechanisms of p53 inactivation -Nitric Oxide inhibits the function of p53 and are associated with p53 mutations (early in ulcerative colitis) -Inflammatory cytokine, IL-6 increases DNA methyltransferase activity resulting in methylation of the p53 promoter yielding decreased transcription of p53

Chk1 and Chromosome Instability -Tumor Suppressor

Chk1 and Chromosome Instability Inhibition of Chk1 -COX2 overexpression activated, AKT, which then inhibited Chk1 through phosphorylation -This is occurring while Chk1 is in a heterozygous state in breast cancer cells -Haploinsufficiency

Rb and Chromosome Instability Rb is a tumor suppressor which inhibits cell growth through transcriptional inhibition of genes needed for S phase of the cell cycle -Nitric Oxide induces hypermethylation of Rb, allowing gene expression -Allows up regulation of Mad2, a spindle checkpoint

Rb and Chromosome Instability -Tumor Suppressor

Double Strand Breaks in DNA Causes DS Breaks: -Ionizing Radiation -Reactive Oxygen Species (ROS) -Reactive Nitrogen Species -Overexpression of c-Myc and Ras

C-Myc and Chromosome Instability Growth factors and chemokines from inflammatory cells induce overexpression of c-Myc C-Myc alters the expression of hundreds of genes resulting in overall cell growth rate, resulting in an increase in double-strand breaks

C-Myc and Chromosome Instability -Oncogene

Double Strand Break Repair Non-homologous end joining is Error Prone Homologous Recombination is Error Free

Inhibition of Homologous Recombination 2 Mechanisms 1. Bcl-2 Overexpression -Bcl-2 is an anti-apoptotic molecule, inhibitor of apoptosis -Bcl-2 is overexpressed through Nf-κB activation -Bcl-2 then inhibits RAD51, a key player in Homologous Recombination 2. HIF-1α Overexpression - HIF-1α is up regulated by inflammatory cytokines - HIF-1α induces miR-210 and miR-373 which down regulates RAD52