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: 8569176
• 负责人: Kounosuke Watabe
• 金额: $ 19.94万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8569176
• 关键词: Affect; Antibodies; Binding; Cancer Patient; Cell Communication; Cells; Chemicals; Co-Immunoprecipitations; Data; Developmental Therapeutics Program; Disease; Disseminated Malignant Neoplasm; Endothelial Cells; Epidermal Growth Factor Receptor; Gene Expression; Genes; Goals; Integral Membrane Protein; Integrins; KAI1 gene; Knockout Mice; Lead; Libraries; Malignant - descriptor; Malignant Neoplasms; Medical Technology; Metastasis Suppression; Metastasis Suppressor Genes; Methods; Molecular; Neoplasm Metastasis; Operative Surgical Procedures; Organ; Patients; Phospho-Specific Antibodies; Primary Neoplasm; Proteins; Proteomics; Role; Screening procedure; Signal Pathway; Signal Transduction; Signaling Molecule; Small Interfering RNA; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Up-Regulation; Western Blotting; base; cancer cell; cancer type; chemotherapy; clinically significant; efficacy testing; in vivo; knock-down; meetings; neoplastic cell; novel; novel therapeutics; protein complex; repository; research study; senescence; small molecule; 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（申请人提供）：超过95%的癌症患者死于转移，这是恶性癌症的标志。尽管最近的手术技术和化疗有了显着改进，但目前的医疗技术都没有“治愈”转移性疾病，并且患有转移性癌症的患者不可避免地会死亡。因此，迫切需要开发针对转移性肿瘤细胞的新型靶向特异性疗法，这需要更全面地了解转移的分子机制。 KAI1基因（也称为CD82）是一种肿瘤转移抑制因子，其表达在多种类型的癌症中显着下调，该基因的过表达能够阻断转移而不影响体内原发肿瘤的生长。然而，转移抑制的确切分子机制尚未得到很好的了解。我们最近发现（i）肿瘤细胞上的 KAI1 与内皮细胞上的 DARC 相互作用，（ii）KAI1-DARC 上调 p21 和下调 TBX2 的相互作用，（iii）TBX2-p21 信号的这种调节导致(iv) DARC 敲除小鼠中 KAI1 的转移抑制活性显着受损。这些结果强调了 DARC 基因先前未被认识的功能，并将 KAI-DARC 信号确定为转移性癌症潜在治疗干预的新候选者。根据我们的初步数据，我们假设 KAI1 与整合素、四跨膜蛋白和 PKC 形成“多蛋白复合物”，并且当癌细胞渗入时，KAI1 与内皮细胞上的 DARC 结合，然后激活/失活 PKC，从而导致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、CD63、CD9 和 PKC）在 KAI1 的转移抑制功能中的作用，(ii) 检查(iii) 通过测试抗 KAI1 抗体和鉴定小化学物质来检查针对 KAI1-DARC 信号的治疗潜力。我们的长期目标是阐明 KAI1 在肿瘤转移抑制中的功能作用，并开发一种模仿 KAI1 基因功能的新型治疗方法。我们相信，所提出的实验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）提供基础信息。

项目成果

Metabolic genes in cancer: their roles in tumor progression and clinical implications.

• DOI: 10.1016/j.bbcan.2010.01.005
• 发表时间: 2010-04
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
• 影响因子: 11.2
• 作者: Furuta, Eiji;Okuda, Hiroshi;Kobayashi, Aya;Watabe, Kounosuke
• 通讯作者: Watabe, Kounosuke

Drug development against metastasis-related genes and their pathways: a rationale for cancer therapy.

• DOI: 10.1016/j.bbcan.2008.07.002
• 发表时间: 2008-12
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
• 影响因子: 11.2
• 作者: Iiizumi, Megumi;Liu, Wen;Pai, Sudha K.;Furuta, Eiji;Watabe, Kounosuke
• 通讯作者: Watabe, Kounosuke

Anti-cancer drugs targeting fatty acid synthase (FAS).

• DOI: 10.2174/157489212799972891
• 发表时间: 2012-05
• 期刊: Recent patents on anti-cancer drug discovery
• 影响因子: 2.8
• 作者: P. Pandey;Wen Liu;F. Xing;K. Fukuda;K. Watabe

Cancer associated fibroblasts (CAFs) in tumor microenvironment.

• DOI: 10.2741/3613
• 发表时间: 2010-01-01
• 期刊: Frontiers in bioscience (Landmark edition)
• 作者: Xing F;Saidou J;Watabe K
• 通讯作者: Watabe K

N-myc downstream regulated gene 1 modulates Wnt-β-catenin signalling and pleiotropically suppresses metastasis.

• DOI: 10.1002/emmm.201100190
• 发表时间: 2012-02
• 期刊: EMBO MOLECULAR MEDICINE
• 影响因子: 11.1
• 作者: Liu, Wen;Xing, Fei;Iiizumi-Gairani, Megumi;Okuda, Hiroshi;Watabe, Misako;Pai, Sudha K.;Pandey, Puspa R.;Hirota, Shigeru;Kobayashi, Aya;Mo, Yin-Yuan;Fukuda, Koji;Li, Yi;Watabe, Kounosuke
• 通讯作者: Watabe, Kounosuke