TGFBETA Signaling in Prostate Cancer Cells

项目总结(见说明)： 非裔美国人男性受前列腺癌的影响不成比例。与高加索男性相比，非洲裔美国男性的前列腺癌发病率高出65%，死亡率高出一倍多。在非裔美国男性中，前列腺癌的诊断也处于更晚期，年龄更早。以往对乳腺癌和子宫内膜癌的研究表明，转化生长因子β3(vs转化生长因子β1)在转移性疾病中起着重要作用。最近的研究表明，在非裔美国人中，外周血转化生长因子-β1蛋白水平与体重指数、微量蛋白尿、血浆肾素活性和代谢综合征有关，但在高加索人中不相关。在患有高血压、糖尿病、青光眼和终末期肾病的高加索患者中，非裔美国人的转化生长因子-β1的过度表达显著高于高加索人。在我们最近的研究中，我们检测了三种转化生长因子-β亚型(-B1、B2和B3)在几种前列腺细胞系中的表达，这些细胞系代表了正常的上皮细胞和不同阶段的癌症进展。这些研究表明，所有细胞系都表达转化生长因子-β1的mRNA和蛋白。另一方面，转化生长因子-β3mRNA和蛋白在正常前列腺上皮细胞中低水平表达，而在代表疾病转移阶段的前列腺癌细胞系中高水平表达。我们的后续研究表明，转化生长因子-β3对前列腺癌细胞的迁移和侵袭行为有显著的影响，并且这种异构体在发挥这些作用方面明显强于转化生长因子-β3。我们还发现，转化生长因子-β3对细胞迁移和侵袭的影响是通过β-3-激酶/AKT信号通路来实现的。这项拨款建议的研究将检验这一假设，即在癌症晚期，转化生长因子-β3的表达增加可能与转移性疾病的快速进展有关。此外，非裔美国人男性体内这种细胞因子水平较高可能是前列腺癌发病率和死亡率增加的原因。这些研究将集中在1)转化生长因子-β亚型表达的测定，2)转化生长因子-β3激活PI3-激酶信号通路，以及3)转化生长因子-β3调节前列腺癌侵袭行为的机制。

PROJECT SUMMARY (See instructions): African-American men are disproportionately affected by prostate cancer. African-American men have 65% higher incidence rate and more than twice the mortality rate due to prostate cancer when compared with Caucasian men. Prostate cancer is also diagnosed at a more advanced stage at an earlier age in African- American men. Previous studies in breast and endometrial cancer suggested an important role of TGF Beta3 (vs TGF Beta1) in metastatic disease. Recent studies have shown that peripheral blood TGF-Beta1 protein levels are associated with body mass index, microalbumuria, plasma renin activity, and metabolic syndrome in African Americans but not in Caucasians. Overexpression of TGF-Beta1 was significantly higher in African- Americans patients than in Caucasian patients with hypertension, diabetes, glaucoma and end stage renal disease. In our recent studies, we determined the expression of three TGF-B isoforms (-B1, B2 and B3) in several prostate cell lines representing normal epithelial cells and various stages of cancer progression. These studies revealed that TGF-Beta1 mRNA and protein were expressed by all cell lines. On the other hand, TGF- Beta3 mRNA and protein are expressed at very low levels in normal prostate epithelial cells but are expressed at very high levels in prostate cancer cell lines representing metastatic stages of the disease. Our continued studies revealed that TGF- Beta3 exerts significant effects on migration and invasive behavior of prostate cancer cells and that this isoform is significantly more potent than TGF- Beta3 in exerting these effects. We also found that these effects of TGF- Beta3 on migration and invasion are mediated by the Beta3-kinase/AKT signaling pathway. The studies proposed in this grant will test the hypothesis that the increased expression of TGF- Beta3 in later stages of cancer may be involved in rapid progression of the metastatic disease. Additionally, higher levels of this cytokine in African-American men may be responsible for increased incidence and mortality due to prostate cancer. These studies will focus on 1) determination of the expression of TGF- Beta isoforms, 2) the activation of PI3-kinase signaling pathway by TGF- Beta3 and, 3) the mechanisms by which TGF-Beta may regulate the invasive behavior of prostate cancer cells.