1. Tumor Promoting Inflammation
Sept 14, 2017

2. Hallmarks of Cancer, 2011

3. Enabling Characteristics
Hallmarks of Cancer, 2011

4. 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

5. 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)

6. 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

7. 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

8. 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

9. DNA Glycosylase Mechanism
Encoded by the AAG gene

10. AP Endonuclease
Encoded by the APE1 gene

11. 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

12. – 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

13. 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?

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

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

18. p53 and Chromosome Instability
-Tumor Suppressor

19. 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

20. Chk1 and Chromosome Instability
-Tumor Suppressor

21. 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

23. 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

24. Rb and Chromosome Instability
-Tumor Suppressor

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

26. 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

27. C-Myc and Chromosome Instability
-Oncogene

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

29. 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