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Bcl-10 Mediates Aberrant NF- k B Activity in Hepatocellular Carcinomas

Bcl-10 Mediates Aberrant NF- k B Activity in Hepatocellular Carcinomas. Nathan Wilds Summer 2004. Introduction. Carcinomas of the liver and hepatic bile duct are 5 th most common GI malignancies and 3 rd most lethal neoplasm of GI tract.

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Bcl-10 Mediates Aberrant NF- k B Activity in Hepatocellular Carcinomas

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  1. Bcl-10 Mediates Aberrant NF-kB Activity in Hepatocellular Carcinomas Nathan Wilds Summer 2004

  2. Introduction • Carcinomas of the liver and hepatic bile duct are 5th most common GI malignancies and 3rd most lethal neoplasm of GI tract. • In the midsouth an increase in HCCs is anticipated due to an increase in Hepatitis B and C infections. • NF-kB is directly involved in normal immune and inflammatory responses, cell proliferation, differentiation, apoptosis, and oncogenesis. • NF-kB is constitutively activated in murine and human HCCs.

  3. What is the mechanism of NF-kB constitutive activation in cancer cells??? Identify crucial upstream and downstream components of the NF-kB Pathway in murine HCCs derived from bitransgenic animals. These animals are a widely used model of liver carcinogenesis.

  4. Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Canonical pathway of NF-kB Activation a b IKK complex NF-kB g IkB NF-kB p p IkB NF-kB IkB p p Cytosol Nuclear translocation Degradation (26S proteosome) p IkB p NF-kB

  5. Gene Array Shows Gene Expression Increasing From Surrounding Liver to Tumor. • Transforming growth factor α • Transforming growth factor β1 • Cytochrome P450 (several variances) • B-cell leukemialymphoma 10 (Bcl-10) • Myeloid cell leukemia sequences • Glucokinase (Gck) • Deoxyribonuclease II alpha (DNase2a) • Procollagen, type IV, a1 • Carboxylesterase 3 (Ces3) • Glutathione transferase

  6. Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Role of Bcl-10 in the NF-kB pathway. a b IKK complex Bcl-10 a b g NF-kB g IkB NF-kB p p IkB NF-kB p IkB p Nuclear translocation Degradation (26S proteosome) p IkB p NF-kB

  7. Bcl-10 is Over Expressed in Tumors When Compared to Dysplastic or Wild-Type Livers. IB: Bcl-10 K562 WEHI t1 t2 t3 t4 t5 ma3 ma2 ma1 wt3 wt2 wt1 IB: Bcl-10 K562 WEHI t6 t7 t8 t4 t5 ma3 ma2 ma1 wt3 wt2 wt1

  8. Bcl-10 Expression in Bitransgenic Mice Comparing Surrounding Liver and Tumor Samples SL T SL T PCR Bcl-10 SL T SL T SL T SL T IB Bcl-10

  9. IKK-γ is Ubiquitinated in Tumor, but Not in Surrounding Liver. + + + IP IKK-γ IB: Ubiquitan IKK-γ SL 223 T

  10. IKKg Regulation of NF-kB Activity none 5ng DC IKKg 50ng DC IKKg

  11. Conclusions • Bcl-10 is overexpressed in tumors relative to surrounding livers as well as dysplastic and wt tumors, • Bcl10 is involved in the uibiquitination of IKK-g in tumor samples, • IKKg regulates NF-kB activity in HCCs. • Future experiments will determine whether Bcl-10 is involved in NF-kB signaling in malignant hepatocytes. email

  12. Acknowledgements • The University of Tennessee Health Science Center, Dept of Pharmacology • ASPET • Dr. Marcello Arsura and all the post-docs in his laboratory; Drs. Swayamjot Kaur, Venkatramen Manickam, and Fang Wang, for all their answers to my “does this look right?” and “what in the world is this?” questions.

  13. Questions???

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