HSP27: A modulator and therapeutic target of SPARC-induced glioma invasion.

HSP27：SPARC 诱导的神经胶质瘤侵袭的调节剂和治疗靶点。

• 批准号: 8659915
• 负责人: SANDRA ANN REMPEL
• 金额: $ 17.57万
• 依托单位: SPECTRUM HEALTH HOSPITALS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-04 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8659915
• 关键词: Actins; Animals; Behavior; Cell Line; Cell Survival; Cells; Cellular Morphology; Clinical; Cysteine; Cytoskeleton; Diagnosis; Extracellular Matrix; Glioblastoma; Glioma; HSPB1 gene; Heat shock proteins; In Vitro; Integrin beta Chains; MAP Kinase Gene; MAPK14 gene; MAPKAPK2 gene; Malignant neoplasm of brain; Mutate; PTEN gene; Patients; Phosphorylation; Property; Proteins; Radiation; Resistance; Signal Pathway; Testing; Time; Tumor Cell Invasion; Tumor Suppressor Genes; chemotherapy; human tissue; in vivo; member; migration; neoplastic cell; protein function; public health relevance; therapeutic target; tumor

DESCRIPTION (provided by applicant): Glioblastomas (GBMs) are the most malignant brain tumors. Patients rarely survive more than a year after the initial diagnosis, primarily due to the highly infiltrative/invasive behavior of these tumors, and their resistance to chemotherapy. The proposed studies arise from our efforts to understand the invasive properties of gliomas as an approach to identify unique therapeutic targets. One of the targets we have identified is Secreted Protein Acidic and Rich in Cysteine (SPARC), which is a matricellular protein that is secreted into the extracellular matrix. We have demonstrated that SPARC is highly expressed in gliomas, and that it promotes glioma invasion in vitro and in vivo. Furthermore, we found that SPARC induces migration and invasion via the activation of p38 MAPK-MAPKAPK2-HSP27 signaling pathway. HSP27 is a member of the small heat shock proteins that function to modulate the actin cytoskeleton and migration. We have demonstrated that inhibition of HSP27 suppresses SPARC-induced changes in cell morphology, migration and invasion in vitro in PTEN- null glioma cells. We have also demonstrated that the re-expression of PTEN, a tumor suppressor gene commonly lost or mutated in glioblastomas, suppresses SPARC-induced migration in vitro and invasion in vivo. We therefore propose that PTEN loss enables SPARC-induced migration and invasion via phosphorylation of HSP27. To test this hypothesis we propose the following aims. SPECIFIC AIM 1: Characterize SPARC- induced activation of HSP27 in the absence or presence of PTEN in cell lines and human tissues. SPECIFIC AIM 2: Determine whether inhibition of HSP27 alone, or in combination with radiation and/or chemotherapy, reduces tumor survival in vitro using tumor cells with different SPARC and PTEN status. SPECIFIC AIM 3: Determine whether inhibition of HSP27 alone, or in combination with radiation and/or chemotherapy, reduces SPARC-induced tumor cell invasion and survival in vivo and increases animal survival, using tumor cells with different PTEN status. We propose that pHSP27 inhibition in the commonly occurring SPARC-positive, PTEN-deleted GBMs can have a significant impact on inhibiting glioma cell invasion and is an important clinical strategy for glioma patients. PUBLIC HEALTH RELEVANCE: SPARC promotes glioblastoma invasion in vitro and in vivo by activating a signaling pathway that increases phosphorylation of HSP27, and PTEN is a tumor suppressor gene that suppresses SPARC-induced migration in vitro and in vivo. We propose that the loss of PTEN, commonly observed in glioblastomas, promotes HSP27 phosphorylation by SPARC, commonly upregulated in glioblastomas. We propose that these studies will demonstrate that pHSP27 inhibition in the commonly occurring SPARC-positive, PTEN-deleted GBMs can have a significant impact on inhibiting glioma cell invasion and is an important clinical strategy for glioma patients.

描述(申请人提供)：胶质母细胞瘤(GBM)是最恶性的脑肿瘤。患者很少在最初诊断后存活超过一年，主要是因为这些肿瘤的高度浸润性/侵袭性行为，以及他们对化疗的抵抗力。这项拟议的研究源于我们努力了解胶质瘤的侵袭性，以此作为识别独特治疗靶点的方法。我们已经确定的靶点之一是分泌性蛋白酸性和富含半胱氨酸(SPARC)，它是一种分泌到细胞外基质中的基质蛋白。我们已经证明SPARC在胶质瘤中高表达，并在体外和体内促进胶质瘤的侵袭。此外，我们还发现SPARC通过激活p38MAPK-MAPKAPK2-HSP27信号通路来诱导细胞的迁移和侵袭。HSP27是小分子热休克蛋白的一员，其功能是调节肌动蛋白的细胞骨架和迁移。我们已经证明，抑制HSP27可以抑制SPARC在体外对PTEN缺失的胶质瘤细胞的细胞形态、迁移和侵袭的影响。我们还证明，在胶质母细胞瘤中常见的肿瘤抑制基因PTEN的重新表达可以抑制SPARC诱导的体外迁移和体内侵袭。因此，我们认为PTEN的缺失通过HSP27的磷酸化使SPARC诱导的迁移和侵袭成为可能。为了验证这一假设，我们提出了以下目标。特异性目的1：研究在细胞系和人体组织中没有或存在PTEN的情况下，SPARC对HSP27的激活作用。特异性目的2：利用具有不同SPARC和PTEN状态的肿瘤细胞，确定单独抑制HSP27或与放射和/或化疗联合使用是否会降低肿瘤的存活率。特异性目的3：利用具有不同PTEN状态的肿瘤细胞，确定单独抑制HSP27，或与放射和/或化疗联合使用，是否可以减少SPARC诱导的肿瘤细胞在体内的侵袭和存活，并增加动物存活。我们认为，在常见的SPARC阳性、PTEN缺失的基底膜中抑制PHSP27可以显著抑制胶质瘤细胞的侵袭，是胶质瘤患者的重要临床策略。 公共卫生相关性：SPARC在体外和体内通过激活信号通路增加HSP27的磷酸化来促进胶质母细胞瘤的侵袭，而PTEN是一种肿瘤抑制基因，在体外和体内抑制SPARC诱导的迁移。我们认为，在胶质母细胞瘤中常见的PTEN的缺失促进了SPARC的HSP27磷酸化，而SPARC在胶质母细胞瘤中通常上调。我们认为，这些研究将证明，在常见的SPARC阳性、PTEN缺失的基底膜中抑制PHSP27可以显著抑制胶质瘤细胞的侵袭，是胶质瘤患者的重要临床策略。