Date of Graduation

5-2016

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Dr. Xin Lin

Committee Member

Dr. Dos Sarbassov

Committee Member

Dr. M. James You

Committee Member

Dr. Chengming Zhu

Committee Member

Dr. Paul Chiao

Abstract

The transcription factor NF-κB plays a central role in many aspects of biological processes and diseases, such as inflammation and cancer. Although it has been suggested thatNF-κB is critical in tumorigenesis and tumor progression, the molecular mechanism by which NF-κB is activated in solid tumor remains largely unknown. In the current work, we focus on growth factor receptor-induced NF-κB activation and tumor progression, including epidermal growth factor receptor (EGFR)-induced NF-κB in lung cancer and heregulin receptor (HER2)-induced NF-κB in breast cancer. We found that Mucosa-associated lymphoma translocation protein 1 (MALT1), also known as paracaspase, is required for EGFR-induced NF-κB activation by recruiting E3 ligase TRAF6 to the IKK complex. In addition, MALT1 also contributes to many malignant phenotypes, including tumor cell proliferation, survival, migration and metastasis. Furthermore, by generating transgenic mice in which EGFR-associated lung adenocarcinoma will be developed in the absence of MATL1, we found that MALT1 specifically contributes to the EGFR- but not K-ras-induced lung adenocarcinoma by activating both NF-κB and STAT3 pathway, suggesting a crucial role of MALT1 in EGFR-associated lung cancer progression. In a separate study, we found that MALT1, together with its interaction partners CARMA3 and BCL10 (also known as the CBM complex), is required for HER2-induced NF-κB activation. Consistently, the CBM complex contributes to malignant phenotypes in breast cancer cells, including proliferation, survival, migration, invasion and metastasis. Furthermore, we showed that the development of mammary tumor was delayed in MALT1-deficient mice (MMTV-Neu; Malt1-/-), indicating that MALT1 contributes to the onset and progression of breast cancer in vivo. To further explore the role of MALT1 in cancer therapy, we found that MALT1 and the CBM complex are involved in resistance of chemotherapy induced apoptosis. MALT1 deficiency promotes doxorubicin-induced apoptosis. Mechanistically, the CBM complex is required for DNA damage-induced NF-κB activation, which antagonizes doxorubicin-induced apoptosis. In summary, our studies have revealed the multi-functional roles of MALT1 and the CBM complex in growth factor-associated solid tumors and cancer therapy.

Keywords

NF-kB, MALT1, CARMA3, Lung Cancer, Breast Cancer, DNA damage, Signal Transduction