FIBRONECTIN REGULATION OF CARCINOMA APOPTOSIS

纤连蛋白对癌细胞凋亡的调节

• 批准号: 7934164
• 负责人: Yvonne L Kapila
• 金额: $ 5.15万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934164
• 关键词: Apoptosis; Apoptotic; Carcinoma; Cell Nucleus; Cell Surface Receptors; Cell Survival; Cell membrane; Cell surface; Cells; Chondroitin Sulfate Proteoglycan; Data; Down-Regulation; Extracellular Matrix; Fibroblasts; Fibronectins; Figs - dietary; Focal Adhesion Kinase 1; Heparin Binding; Integrin alpha4; Integrins; Malignant Epithelial Cell; Mediating; Mutate; PTK2 gene; Pathogenesis; Pathway interactions; Process; Proteins; Proteoglycan; RNA Splicing; Regulation; Resistance; Role; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Squamous cell carcinoma; TP53 gene; Testing; Tumor Cell Biology; Tumorigenicity; c-myc Genes; depressed; insight; keratinocyte; malignant mouth neoplasm; migration; mouth squamous cell carcinoma; neoplastic cell; novel; oral dysplasia; receptor; response; stress-activated protein kinase 1

DESCRIPTION: Fibronectin (FN) and its receptors are important regulatory components in tumor cell survival. We have determined that the carboxyl-terminal heparin-binding domain and alternatively spliced V region of FN are important to this process, since a FN miniprotein (V+H-) containing a mutated heparin-binding domain and the V region of FN induces apoptosis of squamous cell carcinoma (SCC) cells. In contrast, the counterpart wildtype protein (V+H+) or other FN miniproteins not containing the V region promote survival of these cells. Furthermore, in SCC cells, the rate of V+H--mediated apoptosis is delayed compared to normal primary keratinocytes. These data suggest that tumorigenicity has enabled the SCC cells to delay their onset of apoptosis in response to an altered matrix, and that the V region and heparin-binding domain of FN regulate survival of these cells. Our preliminary data suggest that the mechanism by which the V+H- protein induces delayed SCC cell apoptosis may involve chondroitin sulfate proteoglycan and integrin receptors, and p53 and c-myc mediated signals. In primary fibroblasts, this apoptotic mechanism is mediated by a chondroitin sulfate proteoglycan, the alpha4 integrin, and by an intriguing new pathway that requires downregulation of p53 and c-myc. In addition, since p53 relocalizes from the nucleus to the cell membrane in this mechanism, and since the integrin-associated signaling molecule focal adhesion kinase (pp125FAK) and c-Jun N-terminal kinase (JNK) are depressed in this pathway, this suggests that p53 may communicate with integrin/FAK generated signals. We posit that SCC cells resist apoptosis in response to an altered FN matrix (V+H-) via cell surface proteoglycan and integrin receptors. This initiates a signal transduction pathway that leads to downregulation of FAK, p53 and c-myc. Secondarily, because of its important role in regulating SCC cell invasion, migration, and apoptosis, we posit that the V region of FN may be important to SCC cell pathogenesis. We will test these hypotheses in the following Specific Aims: (1) Identify the SCC cell-surface receptors involved in delaying apoptosis induced by the V+H- FN protein in these cells and compare these receptors to those present in primary keratinocytes. (2) Examine the SCC cell signaling response involved in delaying apoptosis induced by the V+H- FN protein. (3) Examine the expression of the alternatively spliced V region of FN in low grade and high-grade oral dysplasia and oral cancer. These studies will help explain some of the cell-matrix interactions and signaling mechanisms that regulate tumor cell biology, and may provide insights into the pathogenesis of oral SCC.

描述：纤连蛋白 (FN) 及其受体是肿瘤细胞存活的重要调节成分。我们已经确定，FN 的羧基末端肝素结合结构域和选择性剪接的 V 区对此过程很重要，因为含有突变的肝素结合结构域和 FN V 区的 FN 小蛋白 (V+H-) 会诱导鳞状细胞癌 (SCC) 细胞凋亡。相反，对应的野生型蛋白 (V+H+) 或不包含 V 区的其他 FN 小蛋白可促进这些细胞的存活。此外，在鳞状细胞癌细胞中，与正常原代角质形成细胞相比，V+H-介导的细胞凋亡速率被延迟。这些数据表明，致瘤性使 SCC 细胞能够延迟其细胞凋亡的发生，以响应基质的改变，并且 FN 的 V 区和肝素结合域调节这些细胞的存活。我们的初步数据表明，V+H-蛋白诱导延迟性鳞状细胞癌细胞凋亡的机制可能涉及硫酸软骨素蛋白聚糖和整合素受体，以及p53和c-myc介导的信号。在原代成纤维细胞中，这种凋亡机制是由硫酸软骨素蛋白聚糖、α4 整合素以及需要下调 p53 和 c-myc 的有趣新途径介导的。此外，由于p53在此机制中从细胞核重新定位到细胞膜，并且由于整合素相关信号分子粘着斑激酶（pp125FAK）和c-Jun N末端激酶（JNK）在该途径中被抑制，这表明p53可能与整合素/FAK产生的信号进行通信。我们假设 SCC 细胞通过细胞表面蛋白聚糖和整合素受体抵抗 FN 基质 (V+H-) 改变而抵抗细胞凋亡。这启动了信号转导途径，导致 FAK、p53 和 c-myc 下调。其次，由于其在调节SCC细胞侵袭、迁移和凋亡中的重要作用，我们推测FN的V区可能对SCC细胞的发病机制很重要。我们将在以下具体目标中检验这些假设：(1) 鉴定参与延迟这些细胞中 V+H-FN 蛋白诱导的细胞凋亡的 SCC 细胞表面受体，并将这些受体与原代角质形成细胞中存在的受体进行比较。 (2)检查参与延迟V+H-FN蛋白诱导的细胞凋亡的SCC细胞信号传导反应。 (3)检测FN可变剪接V区在低度和高度口腔异型增生和口腔癌中的表达。这些研究将有助于解释一些调节肿瘤细胞生物学的细胞-基质相互作用和信号传导机制，并可能为口腔鳞状细胞癌的发病机制提供见解。

项目成果

Magic angle spinning NMR-based metabolic profiling of head and neck squamous cell carcinoma tissues.

• DOI: 10.1021/pr200800w
• 发表时间: 2011-11-04
• 期刊: JOURNAL OF PROTEOME RESEARCH
• 影响因子: 4.4
• 作者: Somashekar, Bagganahalli S.;Kamarajan, Pachiyappan;Danciu, Theodora;Kapila, Yvonne L.;Chinnaiyan, Arul M.;Rajendiran, Thekkelnaycke M.;Ramamoorthy, Ayyalusamy
• 通讯作者: Ramamoorthy, Ayyalusamy

The CS1 segment of fibronectin is involved in human OSCC pathogenesis by mediating OSCC cell spreading, migration, and invasion.

• DOI: 10.1186/1471-2407-10-330
• 发表时间: 2010-06-25
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Kamarajan P;Garcia-Pardo A;D'Silva NJ;Kapila YL
• 通讯作者: Kapila YL

ADAM17-mediated CD44 cleavage promotes orasphere formation or stemness and tumorigenesis in HNSCC.

• DOI: 10.1002/cam4.147
• 发表时间: 2013-12
• 期刊: CANCER MEDICINE
• 影响因子: 4
• 作者: Kamarajan, Pachiyappan;Shin, Jae M.;Qian, Xu;Matte, Bibiana;Zhu, Joey Yizhou;Kapila, Yvonne L.
• 通讯作者: Kapila, Yvonne L.

SIRT3 and cancer: tumor promoter or suppressor?

• DOI: 10.1016/j.bbcan.2011.04.004
• 发表时间: 2011-08
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
• 影响因子: 11.2
• 作者: Alhazzazi, Turki Y.;Kamarajan, Pachiyappan;Verdin, Eric;Kapila, Yvonne L.
• 通讯作者: Kapila, Yvonne L.

Receptor-interacting protein (RIP) and Sirtuin-3 (SIRT3) are on opposite sides of anoikis and tumorigenesis.

• DOI: 10.1002/cncr.27655
• 发表时间: 2012-12-01
• 期刊: CANCER
• 影响因子: 6.2
• 作者: Kamarajan, Pachiyappan;Alhazzazi, Turki Y.;Danciu, Theodora;D'silva, Nisha J.;Verdin, Eric;Kapila, Yvonne L.
• 通讯作者: Kapila, Yvonne L.