Analysis of CXCL12/SDF-1alpha mediated activation of the NF-kappaB signaling pathway in head and neck squamous cell carcinoma.

摘要

Head and neck squamous cell carcinoma (HNSCC) is the 6th most common malignancy worldwide with a five-year survival rate of less than 50%. The most important indicator of patient prognosis is lymph node metastasis, which often predicts locoregional recurrence and distant metastasis. Unfortunately, most individuals with HNSCC are diagnosed with advanced stage disease. Cancer metastasis is a multistep process involving disengagement of malignant cells from the primary tumor, invasion through extracellular matrix components, entry into the bloodstream or lymphatic system, and colonization of secondary organs. The G protein coupled receptor CXCR4, which is overexpressed in the majority of cancer types including HNSCC, has been implicated in the homing of tumor cells to secondary organs in order to establish metastases. Typical sites of tumor cell metastasis, such as the lymph nodes, bone marrow, lungs, and liver express high levels of CXCL12/Stromal Derived Factor-1alpha (SDF-1alpha), the chemokine ligand of CXCR4. Chemokines function to induce the directed migration of cells expressing the appropriate receptors. SDF-1alpha can also activate cell growth and survival signals, facilitate neovascularization, and induce invasion of the tumor microenvironment. Consequently, tumor cells expressing CXCR4 exploit all of these mechanisms to escape the primary tumor and migrate towards specific tissues.Currently, the signaling pathways responsible for SDF-1alpha/CXCR4 mediated invasion and metastasis remain largely unexplored. This thesis work explores the role of the NF-kappaB signaling pathway in SDF-1alpha mediated HNSCC invasion. NF-kappaB transcription factors target genes that promote inflammation, proliferation, survival, invasion, angiogenesis, and metastasis. I show that SDF-1alpha can activate NF-kappaB signaling through the CXCR4 receptor in a PI3K/Akt and MAPK/ERK independent manner in HNSCC. Inhibition of IKKbeta, an upstream regulator of classical NF-kappaB signaling, can significantly impair SDF-1alpha mediated HNSCC invasion. Further, I found that the Carma3Bc110/Malt1 (CBM) complex is involved in the activation of NF-kappaB signaling by SDF-1alpha and that this is likely mediated by PKC isozymes. Blocking the expression of the CBM complex inhibits SDF-1alpha mediated invasion of HNSCC. Together, the findings in this thesis suggest that targeting molecular components upstream of NF-kappaB might provide an important therapeutic opportunity in preventing SDF-1alpha/CXCR4 mediated invasion and metastasis of HNSCC.