P53 in hepatocellular carcinoma
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p53 in hepatocellula Carcinoma
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P53 in hepatocellular carcinoma
- 1. Navaira Arif Zunaira Tanveer Yumna Saeed Haris Munir P53 in Hepatocellular Carcinoma
- 2. Hepatocellular Carcinoma • Most common primary malignant tumor of the liver • Fifth most common cancer among men and the eighth in women • HCC originates from liver cells that make up the lining (epithelial cells) of the liver called hepatocytes. • Commonly associated with cirrhosis
- 4. Molecular Pathogenesis of HCC • Pathogenesis of HCC is multifactorial – Chronic Hepatitis and Liver Cirrhosis – Hemochromatosis – Hepatitis B and C virus – High alcohol consumption – Aflatoxins – Inherited metabolic diseases – Genetic mutation (p53)
- 5. Mechanism of development of HCC Two key mechanisms involved in development of HCC 1. Infectious or tissue damage – Liver cirrhosis following tissue damage 2. Genetic Mutations – mutations occurring in 1 or more oncogenes or tumor suppressor genes Chronic Liver Damage Hepatocyte Regeneration Cirrhosis HCC Genetic Alterations
- 6. p53 • p53 is a tumor suppresser gene – it regulates cell division by keeping cells from growing and dividing in an uncontrolled way • “Guardian of the genome” or “Death star” • Up-regulation/down-regulation in the body may promote cancer • P53 is a transcriptional factor of many other genes thus it interferes with other pathways in order to promote or suppress cancer
- 8. p53 helps in cell repair mechanism
- 9. Activation of p53 Normal Conditions MDM2 p53 p53 Ubiquitination Proteasome degradation Oncogenic Stress ATM Kinases Acetylation Phosphorylation MDM2 MDM2 p53 DNA repair Apoptosis
- 10. Mechanism of activated p53 Oncogenic stress DNA damage Phosphoryltion of serine 15 P21 transcriptional upregulation Cell cycle arrest at G1 phase Activation of apoptotic proteins (BAX) Down- regulation of anti apoptotic proteins Induce apoptosis
- 11. Mutated TP53 • Somatic mutations in TP53 gene are the most common genetic changes found in human cancers – Occur in 50% of cancers • Most TP53 mutations change single amino acids in the p53 protein, which leads to the production of an altered version of the protein – cannot control cell proliferation – unable to trigger apoptosis in cells with mutated or damaged DNA – Damaged DNA accumulate in cells – Cells may continue to divide in an uncontrolled way, leading to tumor growth
- 12. Cellular Outcomes of p53 mutations 1. Loss of wild type activities, i.e., activation of p53 target genes and loss of tumor suppressor function 2. Mutant p53 isoforms can exert dominant- negative effects over wild type p53 expressed from the remaining wild type allele 3. Some mutant p53 isoforms carry new pro- oncogenic activities referred to as “gain-of- function”
- 13. P53 in HCC • Mutation in p53 has been cited in almost 25 to 30% cases of HCC • More than 50% of aflatoxin B1-induced HCC – 45% of HBV-related HCC – 13% of HCV-related HCC • Preferential mutation sites are located within the DNA binding domain of p53, reducing its binding affinity to responsive elements hence, leading to decreased expression of p53 target genes
- 14. 1991 Study A point mutation at the third position of codon 249(Arg to ser) resulting in a G:C to T:A transversion was common in HCC in patients from Africa and China This mutation was strictly specific to countries in which food was contaminated by Aflatoxin B1 and Hepatitis B (HBV) infection
- 15. HBV and HCV as oncoviruses in HCC HBV and HCV Liver Injury Hepatocyte death Tumor initiation Cirrhosis Hepatocarcinoge nesis
- 16. HBx - Commonly Integrated HBV Gene 1. Hbx decreases Tp53 binding to XPB (DNA helicase), hence decrease its transcription 2. HBx transgenic mice have increased G:C to T:A transversions induced by AFB1 3. HBx binds to p53 and inactivates p53- dependent activities – p53 sequence-specific DNA binding activity in vitro – p53- mediated transcriptional activation in vivo – represses the TP53 transcription
- 17. HBx deregulates cell cycle check point controls Blocks p53- mediated apoptosis Proapoptotic ability of p53 is lost Selective Clonal Expansion HCC
- 18. Role of p53 in HCC • A number of TP53 mutant and TP53 wild-type HCC cases were analysed by microarrays – identifying 83 p53-related genes in TP53 mutant HCCs • Cell cycle related genes (CCNG2, BZAP45) and cell proliferation related genes (SSR1, ANXA2, S100A10 and PTMA) were overexpressed in mutant TP53 tumors compared with wild-type TP53 tumors
- 19. Other Pathways
- 20. HCV Infection Inactivation/ Reduction of the tumor suppressor KLF6 MDM2 p53 Decreased survival in patients with surgically resected HCC Imbalance in MDM2-p53 pathway
- 21. SRF Stimulate Enigma LIM Increase MDM2 ubiquitin ligase activity and p53 degradation Serum response factor (Overexpressed in HCC)
- 22. PRL-1 Phosphatase of regenerating liver 1 MDM2 phosphorylation through Akt signaling induce Down-regulated p53 levels Inhibited p53-mediated apoptosis
- 23. INGI • Acts as tumor suppressor by inhibiting hepatoma cell proliferation through the induction of apoptosis and cell cycle arrest • Inhibit MDM2 and increase in p53 acetylation and activation • Hence, plays protective role in HCC development SIRT 3 • Control of metabolic activity and deregulation of cancer cell metabolism • Overexpression of SIRT 3 inhibit HCC cell growth and induce apoptosis • Downregulated in HCC
- 25. Concluding Remarks • p53 can be regulated to prevent liver cancer • Inhibition of MDM2-p53 binding could reactivate p53 in cancer cells with WT p53 and may offer an effective therapeutic approach for millions of cancer patients • Introduction of molecules that stabilize the active conformation of the p53 protein and prevents it from degradation
Editor's Notes
- Approximately 80% of primary liver cancers are HCCs Cirrhosis is a late stage of scarring (fibrosis) of the liver caused by many forms of liver diseases and conditions, such as hepatitis and chronic alcoholism. Each time your liver is injured — whether by disease, excessive alcohol consumption or another cause — it tries to repair itself.
- Hemochromatosis = a disorder where too much iron builds up in your body. Sometimes it's called “iron overload
- The name is due to its molecular mass: it is in the 53 kilodalton fraction of cell proteins.
- When the DNA in a cell becomes damaged by agents such as toxic chemicals, radiation, or ultraviolet (UV) rays from sunlight, this protein plays a critical role in determining whether the DNA will be repaired or the damaged cell will self-destruct (undergo apoptosis). If the DNA can be repaired, p53 activates other genes to fix the damage. If the DNA cannot be repaired, this protein prevents the cell from dividing and signals it to undergo apoptosis. By stopping cells with mutated or damaged DNA from dividing, p53 helps prevent the development of tumors.
- p53 is maintained at low protein levels during times of homeostasis, when the cell is not exposed to stress or DNA-damaging events, by its predominant negative regulator Mdm2 through the ubiquitin-proteasome pathway. The Mdm2 E3 ubiquitin ligase represses p53 protein levels through continuous ubiquitination and degradation. The Mdm2-p53 interaction is inhibited by stress-induced acetylation and phosphorylation on Mdm2 by the kinases ATM and c-Abl. A number of phosphorylationand acetylation sites on p53 have been described and many serve to disrupt the Mdm2-p53 interaction as well. Once activated, p53 will induce a cell cycle arrest to allow either repair and survival of the cell or apoptosis. Activated p53 binds DNA and activates expression of several genes including WAF1/CIP1 encoding for p21. p21 (WAF1) binds to the G1-S/CDK (CDK2) and S/CDK complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity. When p21(WAF1) forms a complex with CDK2 the cell cannot continue to the next stage of cell division. A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division.
- positive association between the 249ser mutation of TP53 and AFB1 exposure , The combination of HBV and AFB1 exposure may be TP53 mutations and HCC SP Hussain et al 2167 Oncogene critical to the high frequency of TP53 249ser mutations in HCC
- HBV HCV = hepatitis viruses
- XPB (xeroderma pigmentosum type B) is an ATP-dependent DNA helicase in humans that is a part of the TFIIH transcription factor complex.
- KLF6 is a member of the Krüppel-like C2H2 zinc finger family, which has been shown to be involved with cell cycle regulation, signal transduction, and cell differentiation
- found that the Enigma LIM domain protein, which is involved in signal transduction through protein kinases, can increase MDM2 ubiquitin ligase activity and p53 degradation (34). Furthermore, Enigma can be stimulated by serum response factor (SRF), which is also overexpressed in HCC and leads to further MDM2 stabilization and p53 degradation
- Min et al. showed that one p53 target gene, phosphatase of regenerating liver 1 (PRL-1), that is overexpressed in a variety of cancers through an unknown mechanism, strongly down-regulated p53 levels and inhibited p53-mediated apoptosis by inducing MDM2 phosphorylation through Akt signaling, which forms another feedback loop contributing to HCC development