TGFBETA Signaling in Prostate Cancer Cells

前列腺癌细胞中的 TGFBETA 信号传导

• 批准号: 8552127
• 负责人: Shafiq A Khan
• 金额: $ 15.74万
• 依托单位: CLARK ATLANTA UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552127
• 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 health disparity; cell motility; cytokine; health disparity; human TGFB1 protein; malignant breast neoplasm; men; migration; mortality; outcome forecast; overexpression; peripheral blood; prostate cancer cell; 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（请参阅说明）： 非裔美国人受到前列腺癌的影响不成比例。与高加索男性相比，非裔美国人的发病率高65％，而由于前列腺癌引起的死亡率的两倍以上。在非洲裔美国男性的年龄较早的时候，在更先进的阶段也被诊断出前列腺癌。先前在乳腺癌和子宫内膜癌的研究表明，TGF Beta3（VS TGF Beta1）在转移性疾病中起着重要作用。最近的研究表明，外周血TGF-BETA1蛋白水平与非洲裔美国人的体重指数，微量白蛋白酶，血浆肾素活性和代谢综合征有关，而在高加索人中则无关。非裔美国人患者的TGF-BETA1的过表达明显高于高血压患者，糖尿病，青光眼和末期肾脏疾病。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的各个阶段的几个前列腺细胞系中三个TGF-B同工型（-b1，b2和b3）的表达。这些研究表明，TGF-BETA1 mRNA和蛋白质均由所有细胞系表达。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，但在代表该疾病转移性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入性行为产生重大影响，并且该同工型在发挥这些作用时比TGF-Beta3明显更有效。我们还发现，TGF-β3对迁移和侵袭的这些影响是由Beta3-激酶/AKT信号通路介导的。该赠款中提出的研究将检验以下假设：在癌症后期，TGF-BETA3的表达增加可能与转移性疾病的快速发展有关。此外，非裔美国人男性中这种细胞因子的较高水平可能导致因前列腺癌引起的发病率和死亡率增加。这些研究将重点放在1）确定TGF-β同工型的表达，2）通过TGF-BETA3和3）TGF-BETA可能调节前列腺癌的侵入性行为的机制激活PI3-激酶信号传导途径。细胞。