SOX9 in prostate cancer development and progression

SOX9 在前列腺癌发生和进展中的作用

• 批准号: 8233930
• 负责人: Xin Yuan
• 金额: $ 35.41万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-19 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233930
• 关键词: Adult; Androgens; Basal Cell; Biological Markers; Blood Vessels; Cell Cycle; Cell Proliferation; Cells; Clinical; Critical Pathways; Data; Development; Developmental Gene; Down-Regulation; Doxycycline; Epithelial Cells; Epithelium; Erinaceidae; Extracellular Matrix; Extracellular Matrix Proteins; Gene Expression; Gene Targeting; Generations; Genes; Goals; Growth; Growth Factor; Homeostasis; Hormones; Human; In Vitro; LNCaP; Lead; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mediator of activation protein; Metastatic Prostate Cancer; Molecular; Mus; Oligonucleotide Microarrays; Organogenesis; PC3 cell line; Pathway interactions; Patients; Production; Prostate; Proteins; Recurrence; Refractory; Role; Sampling; Signal Pathway; Site; Small Interfering RNA; Tetracyclines; Up-Regulation; Xenograft procedure; angiogenesis; cancer cell; cancer therapy; fetal; gene function; in vivo; insight; neoplastic cell; prognostic; public health relevance; response; smoothened signaling pathway; transcription factor; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Cancers frequently exploit developmental genes/pathways to sustain their uncontrolled growth and invasion. To study the molecular mechanisms of prostate cancer (PCa) progression, we are focusing on the potential role of SOX9, an important developmental transcription factor. We have discovered that SOX9 is expressed in human fetal prostate epithelial cells and in the basal cells of adult prostate, suggesting it is involved in prostate organogenesis and homeostasis. Significantly, SOX9 is also expressed in primary and metastatic prostate cancer (PCa) in vivo and in PCa cell lines in vitro. Its expression is further increased in hormone refractory recurrent PCa, suggesting SOX9 is a potential biomarker for more aggressive PCa. SOX9 over-expression in LNCaP PCa cell renders cancer cells more efficiently establish in vivo xenografts and local invasion in mice. These xenografts accumulates extracellular matrix (ECM) and carry a vast vascular network, suggesting SOX9 promotes tumor growth by inducing tumor ECM production and angiogenesis. Microarray analyses of SOX9 regulated genes in response to SOX9 over-expression in LNCaP cells has selected several potential targets that are involved in cell proliferation, ECM formation and angiogenesis. Down-regulation of endogenous SOX9 by siRNA decreases cell proliferation and causes a cell cycle shift to G0/G1 in PCa cell lines and a reduced growth in PCa xenografts. Our studies further show that SOX9 expression in PCa cells is regulated by the Wnt/2-catenin, hedgehog (Hh), and androgen signaling pathways, suggesting SOX9 may be an important mediator of these critical pathways for prostate development and homeostasis, and for PCa growth and progression. These data suggest that SOX9, as a transcriptional factor, regulates genes (such as EMC proteins, proangiogenic factor or growth factors) expressed in basal cells that are critical to support the generation or survival of secretory epithelial cells in normal prostate. In PCa, dysregulated SOX9 expression allows the tumor cells to grow at local and metastatic sites in the absence of basal cell support. The overall goal of this proposal is to define the molecular mechanisms of SOX9 functions by identifying and validating SOX9 regulated genes or pathways in PCa cell lines, xenografts and patient samples. SOX9 function in PCa establishment and growth will be investigated through specific up- or down-regulating SOX9 expression in PCa cells and tumors. Finally, SOX9 and its target gene expression in PCa will be interrogated for its correlation with PCa establishment and progression as well as its potential as a prognostic biomarker. This study will not only provide insight in the molecular mechanisms of SOX9 functions in development and homeostasis of normal prostate, as well as in the tumorigenesis and progression of PCa. Public Health Relevance: We will study the functions of SOX9 in prostate development, maintenance and prostate cancer development and progression. Our results will lead to a better understanding of the molecular mechanisms of SOX9 function and identify potential targets for cancer therapy.

描述（由申请人提供）：癌症经常利用发育基因/途径来维持其不受控制的生长和侵袭。为了研究前列腺癌 (PCa) 进展的分子机制，我们重点关注重要的发育转录因子 SOX9 的潜在作用。我们发现SOX9在人胎儿前列腺上皮细胞和成人前列腺基底细胞中表达，表明它参与前列腺器官发生和体内平衡。值得注意的是，SOX9 还在体内原发性和转移性前列腺癌 (PCa) 以及体外 PCa 细胞系中表达。它的表达在激素难治性复发性 PCa 中进一步增加，表明 SOX9 是更具侵袭性 PCa 的潜在生物标志物。 LNCaP PCa 细胞中 SOX9 的过表达使癌细胞能够更有效地在小鼠体内建立异种移植物和局部侵袭。这些异种移植物积累细胞外基质 (ECM) 并携带巨大的血管网络，表明 SOX9 通过诱导肿瘤 ECM 产生和血管生成来促进肿瘤生长。 LNCaP 细胞中响应 SOX9 过度表达的 SOX9 调节基因的微阵列分析选择了几个参与细胞增殖、ECM 形成和血管生成的潜在靶点。 siRNA 下调内源性 SOX9 会降低细胞增殖，导致 PCa 细胞系中的细胞周期转变为 G0/G1，并导致 PCa 异种移植物的生长减少。我们的研究进一步表明，PCa 细胞中的 SOX9 表达受到 Wnt/2-catenin、hedgehog (Hh) 和雄激素信号通路的调节，表明 SOX9 可能是前列腺发育和稳态以及 PCa 生长和进展的这些关键通路的重要介质。这些数据表明，SOX9 作为转录因子，调节基底细胞中表达的基因（例如 EMC 蛋白、促血管生成因子或生长因子），这些基因对于支持正常前列腺中分泌性上皮细胞的生成或存活至关重要。在前列腺癌中，SOX9 表达失调使肿瘤细胞在缺乏基底细胞支持的情况下在局部和转移部位生长。该提案的总体目标是通过识别和验证 PCa 细胞系、异种移植物和患者样本中 SOX9 调节的基因或通路来定义 SOX9 功能的分子机制。将通过特异性上调或下调 PCa 细胞和肿瘤中的 SOX9 表达来研究 SOX9 在 PCa 建立和生长中的功能。最后，SOX9 及其在 PCa 中的靶基因表达将被询问其与 PCa 建立和进展的相关性以及其作为预后生物标志物的潜力。这项研究不仅将深入了解 SOX9 在正常前列腺发育和稳态以及 PCa 肿瘤发生和进展中的分子机制。公共健康相关性：我们将研究 SOX9 在前列腺发育、维持以及前列腺癌发生和进展中的功能。我们的结果将有助于更好地理解 SOX9 功能的分子机制并确定癌症治疗的潜在靶点。