| CXCL1 is a CXC chemokine involved in a variety of physiological and pathological processes such as inflammation, angiogenesis, and tumorigenesis. The diverse functions of CXCL1 suggest that determining the regulation of CXCL1 is an important part of understanding its role in these processes. Thus far, the control of CXCL1 during tumorigenesis is poorly understood.; This dissertation research was undertaken to investigate the regulation of murine CXCL1 (KC) by two tumor promotion-related molecules, okadaic acid (OKA) and osteopontin (OPN). OKA is a natural toxin that inhibits phosphatases 1 and 2A and a potent tumor promoter shown to induce tumorigenesis. OPN is a matrix protein and is required for tumor promoter-induced tumorigenesis. However, very little is known on the mechanisms by which OPN or OKA regulates the process of tumorigenesis. The present study examine whether OKA and OPN regulate KC expression, which might mediate tumorigenesis, using an in vitro tumor promotion model, JB6 C141.5a cells.; The major findings of this research are as follows: (1) OPN stimulated the expression of CXCL1/KC; (2) induction of CXCL1/KC was responsive to different species OPN but not to other arginine-glycine-aspartate-containing matrix proteins; (3) transactivation of the KC promoter by OPN was not mediated through nuclear factor-kappaB (NF-kappaB) and activator complex protein 1; (4) extracellular signal-regulated kinase was the main mediator for OPN-induced CXCL1/KC expression; (5) OKA induced CXCL1/KC expression; (6) the induction of CXCL1/KC by OKA was mediated through NF-kappaB; (7) there are two NF-kappaB response elements in the KC promoter, kappaB1 and kappaB2, of which kappaB1 had a higher binding affinity to NF-kappaB; (8) the NF-kappaB complex activated by OKA consisted of a dimer from the subunits p65, p50, and c-Rel, in which p65 is the major subunit and c-Rel or p50 is the other minor partner; and (9) antioxidants and potential chemopre-ventive agents epigallocatechin gallate and grape seed extract suppressed OKA-induced CXCL1/KC expression.; These results provide direct evidence of the control of CXCL1/KC by tumor promotion-related molecules, suggesting its potential role in tumor promotion. These results also provide insights into how various natural dietary agents may be useful substances in suppressing tumorigenesis. |
