SOX9 in prostate cancer development and progression

描述(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。为了研究前列腺癌进展的分子机制，我们将重点放在SOX9的潜在作用上，SOX9是一个重要的发育转录因子。我们发现SOX9在人胎儿前列腺上皮细胞和成人前列腺的基底层细胞中均有表达，提示其参与了前列腺的器官发生和动态平衡。值得注意的是，SOX9在体内原发癌和转移性前列腺癌以及体外前列腺癌细胞系中也有表达。在激素难治性复发性PCa中，SOX9的表达进一步增加，提示SOX9可能是更具侵袭性的PCa的潜在生物标志物。SOX9在LNCaP PCA细胞中的过表达使癌细胞能够更有效地建立体内异种移植和小鼠的局部侵袭。这些异种移植瘤积聚了细胞外基质(ECM)，并携带了大量的血管网络，提示SOX9通过诱导肿瘤ECM的产生和血管生成来促进肿瘤的生长。SOX9调控基因在LNCaP细胞中过表达的微阵列分析已经选择了几个与细胞增殖、细胞外基质形成和血管生成有关的潜在靶点。SiRNA下调内源性SOX9可抑制细胞增殖，导致PCa细胞系细胞周期向G0/G1期转变，并抑制PCa异种移植瘤的生长。我们的研究进一步表明，SOX9在前列腺癌细胞中的表达受Wnt/2-catenin、hedgehog(HH)和雄激素信号通路的调节，这表明SOX9可能是这些促进前列腺发育和动态平衡以及前列腺癌生长和进展的关键通路的重要中介。这些数据表明，SOX9作为一种转录因子，调节在基底层细胞中表达的基因(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分泌上皮细胞的生成或存活至关重要。在前列腺癌中，SOX9表达异常允许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。这项建议的总体目标是通过在前列腺癌细胞系、异种移植瘤和患者样本中识别和验证SOX9调控的基因或途径来确定SOX9功能的分子机制。SOX9在前列腺癌的建立和生长中的作用将通过上调或下调SOX9在前列腺癌细胞和肿瘤中的表达来研究。最后，SOX9及其靶基因在PCa中的表达将被问及它与PCa的建立和发展的相关性以及它作为预后生物标志物的潜力。本研究不仅对SOX9功能在正常前列腺发育和动态平衡中的分子机制以及在前列腺癌的发生和发展中的作用提供了深入的研究。公共卫生相关性：我们将研究SOX9在前列腺发育、维持和前列腺癌发生发展中的作用。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。

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.