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中重要的调节成分。我们已经确定，羧基末端肝素结合结构域和FN的剪接V区域对此过程很重要，因为含有突变的肝素结合结构域的FN微型蛋白（V+H-）和FN的V区域诱导了鳞状细胞癌（SCC）细胞的凋亡。相反，对应物野生型蛋白（V+H+）或其他不包含V区域的FN小蛋白会促进这些细胞的存活。此外，在SCC细胞中，与正常的原代角质形成细胞相比，V+H-介导的凋亡的速率被延迟。这些数据表明，肿瘤性使SCC细胞能够响应改变的基质而延迟其细胞凋亡的发作，并且FN的V区和FN的V区和肝素结合结构域调节这些细胞的存活率。我们的初步数据表明，V+H蛋白诱导延迟的SCC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。在原发性成纤维细胞中，该凋亡机制是由硫酸软骨蛋白蛋白聚糖，α4整合素以及需要下调p53和c-Myc的有趣的新途径介导的。 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.我们认为，SCC细胞会通过细胞表面蛋白聚糖和整合素受体响应改变的FN基质（V+H-）抗凋亡。这启动了信号转导途径，导致FAK，p53和c-myc的下调。其次，由于其在调节SCC细胞侵袭，迁移和凋亡中的重要作用，我们认为FN的V区域对SCC细胞发病机理可能很重要。我们将在以下特定目的中检验这些假设：（1）确定这些细胞中V+H- FN蛋白诱导的凋亡涉及的凋亡的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）检查延迟V+H-FN蛋白诱导的细胞凋亡所涉及的SCC细胞信号反应。 （3）检查低年级和高级口服发育不良和口腔癌中FN的剪接V区域的表达。这些研究将有助于解释调节肿瘤细胞生物学的一些细胞 - 矩阵相互作用和信号传导机制，并可能提供有关口服SCC发病机理的见解。

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

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.

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

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.