Functional role of tumor metastases suppressor gene, KAl1, in tumor progression

肿瘤转移抑制基因 KAl1 在肿瘤进展中的功能作用

• 批准号: 7934045
• 负责人: Kounosuke Watabe
• 金额: $ 3.41万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934045
• 关键词: Affect; Antibodies; Binding; Cancer Patient; Chemicals; Data; Disease; Disseminated Malignant Neoplasm; Endothelial Cells; Epidermal Growth Factor Receptor; Gene Expression; Genes; Goals; Integrins; KAI1 gene; Knockout Mice; Lead; Malignant - descriptor; Malignant Neoplasms; Medical Technology; Metastasis Suppression; Metastasis Suppressor Genes; Methods; Molecular; Neoplasm Metastasis; Operative Surgical Procedures; Patients; Primary Neoplasm; Role; Signal Pathway; Signal Transduction; Techniques; Testing; Therapeutic; Therapeutic Intervention; Up-Regulation; base; cancer cell; cancer type; chemotherapy; in vivo; meetings; neoplastic cell; novel; novel therapeutics; protein complex; research study; senescence; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): More than 95% of cancer patients succumb to the disease due to metastases which is the hallmark of malignant cancer. Despite significant improvements in recent surgical techniques and chemotherapies, none of the current medical technologies "cure" the metastatic disease, and the patients who have acquired metastatic cancer inevitably die. Therefore, there is an urgent need for developing a novel target-specific therapy to metastatic tumor cells, which requires more comprehensive understanding of the molecular mechanism of metastases. The KAI1 gene (also called CD82), is a tumor metastases suppressor whose expression is significantly down-regulated in various types of cancers, and over-expression of this gene is capable of blocking metastases without affecting the primary tumor growth in vivo. However, the exact molecular mechanism of the metastases suppression has not been well understood. We have recently found that (i) KAI1 on tumor cells interacts with DARC on endothelial cell, (ii) the interaction of KAI1-DARC up-regulated p21 and down-regulated TBX2, (iii) this modulation of TBX2-p21 signal lead to senescence of tumor cell, and (iv) metastases suppressor activity of KAI1 is significantly compromised in DARC knockout mouse. These results highlight a previously unappreciated function of the DARC gene and identified the KAI-DARC signal as a novel candidate for potential therapeutic intervention for metastatic cancer. Based on our preliminary data we hypothesize that KAI1 forms a "multi-protein complex" with integrins, tetraspanins and PKC and that when the cancer cell intravasates, KAI1 binds to DARC on an endothelial cell followed by activation/inactivation of PKC, which results in up-regulation of p21 and induction of senescence of the cancer cell. To test this hypothesis, we will (i) examine the role of each factor of the multi-protein complex including integrins, kitenin, EGFR, c-Met, CD63, CD9 and PKC in the metastasis suppressor function of KAI1, (ii) examine the signal pathway of senescence induced by KAI1-DARC interaction and (iii) examine therapeutic potential of targeting KAI1-DARC signal by testing anti-KAI1 antibody and also by identifying small chemicals. Our long-term goal is to elucidate the functional role of KAI1 in tumor metastases suppression and to develop a novel therapeutic method which mimics the function of the KAI1 gene. We believe that the results of the proposed experiments should provide fundamental information to accomplish our ultimate goal, the control of tumor metastasis in cancer patients.

描述（由申请人提供）：超过95%的癌症患者由于转移而死于该疾病，转移是恶性癌症的标志。尽管最近的手术技术和化疗有了显著的改进，但目前的医疗技术都不能“治愈”转移性疾病，获得转移性癌症的患者不可避免地死亡。因此，迫切需要开发一种针对转移性肿瘤细胞的新型靶向特异性治疗方法，这需要对转移的分子机制有更全面的了解。KAI 1基因（也称为CD 82）是一种肿瘤转移抑制因子，其表达在各种类型的癌症中显著下调，并且该基因的过表达能够阻断转移而不影响体内原发性肿瘤生长。然而，转移抑制的确切分子机制尚未得到很好的理解。我们最近发现（i）肿瘤细胞上的KAI 1与内皮细胞上的DARC相互作用，（ii）KAI 1-DARC的相互作用上调p21和下调TBX 2，（iii）TBX 2-p21信号的这种调节导致肿瘤细胞衰老，和（iv）KAI 1的转移抑制活性在DARC敲除小鼠中显著受损。这些结果突出了DARC基因以前未被重视的功能，并将KAI-DARC信号鉴定为转移性癌症潜在治疗干预的新候选者。基于我们的初步数据，我们假设KAI 1与整联蛋白、四跨膜蛋白和PKC形成“多蛋白复合物”，并且当癌细胞内渗时，KAI 1与内皮细胞上的DARC结合，随后激活/失活PKC，这导致p21上调并诱导癌细胞衰老。为了检验这一假设，我们将（i）检查多蛋白复合物的每个因子包括整合素、kitenin、EGFR、c-Met、CD 63、CD 9和PKC在KAI 1的转移抑制功能中的作用，（ii）检查由KAI 1-DARC相互作用诱导的衰老的信号通路，和（iii）通过测试抗-DARC抗体来检查靶向KAI 1-DARC信号的治疗潜力。KAI 1抗体，还通过识别小的化学物质。我们的长期目标是阐明KAI 1在肿瘤转移抑制中的功能作用，并开发一种模拟KAI 1基因功能的新治疗方法。我们相信，拟议实验的结果应该为实现我们的最终目标（控制癌症患者的肿瘤转移）提供基本信息。