TGFBETA Signaling in Prostate Cancer Cells

前列腺癌细胞中的 TGFBETA 信号传导

• 批准号: 8544040
• 负责人: Shafiq A Khan
• 金额: $ 16.93万
• 依托单位: CLARK ATLANTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-05 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544040
• 关键词: 1-Phosphatidylinositol 3-Kinase; AKT Signaling Pathway; Advanced Development; Affect; African American; Age; Behavior; Blood specimen; Body mass index; Cancer Patient; Caucasians; Caucasoid Race; Cell Line; Cell Proliferation; Cells; Development; Diabetes Mellitus; Diagnosis; Diagnostic Neoplasm Staging; Disease; Education; End stage renal failure; Endometrial Carcinoma; Epithelial Cells; Extracellular Matrix; Extracellular Matrix Degradation; Glaucoma; Grant; Growth; Hypertension; Immigration; Immunohistochemistry; Immunosuppression; Incidence; Instruction; Malignant neoplasm of prostate; Matrix Metalloproteinases; Mediating; Messenger RNA; Metabolic syndrome; Metastatic to; Microalbuminuria; Molecular; Mutation; Neoplasm Metastasis; PC3 cell line; PTEN gene; Patients; Phosphotransferases; Plasma; Process; Prostate; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Renin; Resistance; Role; Services; Signal Pathway; Signal Transduction; Staging; TGFB1 gene; TGFB3 gene; Testing; Tissue Sample; Transforming Growth Factor beta; Transforming Growth Factors; Tumor Promoters; Tumor Suppressor Proteins; advanced disease; angiogenesis; anticancer research; cancer cell; cancer health disparity; cell motility; cytokine; health disparity; human TGFB1 protein; malignant breast neoplasm; men; migration; mortality; outcome forecast; overexpression; peripheral blood; receptor; response; transforming growth factor beta3; tumor progression

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.

项目摘要（参见说明）： 非裔美国男性受前列腺癌的影响尤为严重。与白人男性相比，非裔美国男性的前列腺癌发病率高出 65%，死亡率是白人男性的两倍多。在非裔美国男性中，前列腺癌在较早的年龄阶段也被诊断为晚期。先前针对乳腺癌和子宫内膜癌的研究表明 TGF Beta3（相对于 TGF Beta1）在转移性疾病中发挥重要作用。最近的研究表明，外周血 TGF-Beta1 蛋白水平与非裔美国人的体重指数、微量白蛋白、血浆肾素活性和代谢综合征相关，但与白种人无关。非洲裔美国人患者中 TGF-Beta1 的过度表达显着高于患有高血压、糖尿病、青光眼和终末期肾病的白种人患者。在我们最近的研究中，我们确定了代表正常上皮细胞和癌症进展各个阶段的几种前列腺细胞系中三种 TGF-B 同工型（-B1、B2 和 B3）的表达。这些研究表明所有细胞系均表达 TGF-Beta1 mRNA 和蛋白质。另一方面，TGF-Beta3 mRNA和蛋白质在正常前列腺上皮细胞中以非常低的水平表达，但在代表疾病转移阶段的前列腺癌细胞系中以非常高的水平表达。我们的持续研究表明，TGF-Beta3 对前列腺癌细胞的迁移和侵袭行为具有显着影响，并且该亚型在发挥这些作用方面比 TGF-Beta3 明显更有效。我们还发现 TGF-Beta3 对迁移和侵袭的这些影响是由 Beta3-激酶/AKT 信号通路介导的。本次资助中提出的研究将检验以下假设：癌症晚期阶段 TGF-β3 表达增加可能与转移性疾病的快速进展有关。此外，非洲裔美国男性中这种细胞因子的水平较高可能是前列腺癌发病率和死亡率增加的原因。这些研究将集中于 1) TGF-Beta 异构体表达的测定，2) TGF-Beta3 对 PI3 激酶信号通路的激活，3) TGF-Beta 调节前列腺癌侵袭行为的机制细胞。