15-lipoxygenase products in colorectal differentiation

描述(由申请者提供)：这项博士后培训计划评估了15-脂氧合酶(15-Lox)的表达通过激活过氧化体增殖物激活受体(PPAR)γ和α来介导结直肠癌细胞分化的假说。实验将利用Caco-2结肠癌细胞系，其中15-Lox在自发分化过程中高度上调。有趣的是，15-Lox产物在Caco-2分化中的作用尚未确定。实验将专门研究15-Lox产物15-HETE和15-HETE-G在促进Caco-2细胞向肠细胞分化方面的贡献。15-HETE和15-HETE-G先前已被证明分别激活PPARGamma和PPARpha转录因子，它们在许多细胞类型的生长抑制和分化中发挥既定的作用。因此，实验将进一步探索15-Lox活性、15-HETE和15-HETE-G的产生在PPAR激活中的作用。还将研究个别PPAR在分化过程中的作用。这项研究将是对15-HETE-G生物学作用的第一次测试。此外，它还将评估15-Lox和PPAR在促进结直肠癌生长抑制方面的作用，为癌症生物学机制提供新的见解。

DESCRIPTION (provided by applicant): This postdoctoral training proposal evaluates the hypothesis that expression of 15-Lipoxygenase (15-Lox) mediates the differentiation of colorectal cancer cells, via the activation of peroxisome proliferator activated receptors (PPAR) gamma and alpha. Experiments will utilize the Caco-2 colon carcinoma cell line, in which 15-Lox is highly upregulated during spontaneous differentiation. Interestingly, a function for 15-Lox products in Caco-2 differentiation has yet to be established. Experiments will specifically address the contribution of the 15-Lox products, 15-HETE and 15-HETE-G in promoting the differentiation of Caco-2 cells into enterocytes. 15-HETE and 15-HETE-G have previously been demonstrated to activate PPARgamma and PPARalpha, respectively, transcription factors with established roles in growth-arrest and differentiation in a number of cell types. Therefore, experiments will further explore the contribution of 15-Lox activity, and 15-HETE and 15-HETE-G production in PPAR activation. The roles of individual PPARs in the differentiation process will also be examined. This research will be the first test for a biological role of 15-HETE-G. In addition, it will evaluate the role of 15-Lox and PPARs in promoting growth arrest in colorectal cancer, providing novel insight into the mechanisms of cancer biology.