REGULATION OF TUMOR DEVELOPMENT BY THE UBIQUITIN LIGASE ITCH

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 尽管在筛查、早期发现和切除癌前息肉方面取得了进展，但结直肠癌仍然是所有美国人癌症死亡的第二大原因。因此，许多研究致力于识别肿瘤特异性分子，这些分子可能是风险疗法的靶点，并可以很容易地与当前使用的化疗方案相结合。我们在这里提出的假设是，瘙痒是Nedd4样泛素连接酶家族的成员，是新辅助治疗的可行候选者。已证明它在间变性甲状腺癌中被扩增，体外抑制Itch通过促进药物治疗后的细胞凋亡来增强化疗药物在各种癌症细胞系中的作用。我们证明了Itch在体内引发肠腺瘤中起着关键作用，缺乏Ich的ApcMin/+小鼠的肿瘤负担减少了71%。我们假设，缺乏Itch的上皮细胞(尤其是肿瘤细胞)对TXNIP、p63或p73介导的细胞凋亡更敏感。我们将通过以下方式验证这一假设：1)通过骨髓移植确定Itch在上皮和免疫系统中所扮演的角色；2)使用条件基因敲除方法描绘ApcMin/+来源的肿瘤对Itch缺失敏感的窗口；以及3)使用Q-PCR、Western blotting和免疫组织化学分析来表征真正的Itch靶点TXNIP、p63和p73在正常组织和肿瘤与5-氟尿嘧啶治疗的组织中的表达。这里产生的数据将为开发这种新的潜在辅助疗法提供关键的理论基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Despite progress made in screening, early detection, and removal of precancerous polyps, colorectal cancer remains the second leading cause of cancer death in all Americans. Consequently, much research is dedicated to identifying tumor-specific molecules that might be targeted in advujant therapies and could be readily combined with currently used chemotherapy regimes. We present here the hypothesis that ITCH, a member of the Nedd4-like family of ubiquitin ligases, is a viable candidate for neoadjuvant therapies. It has been shown to be amplified in anaplastic thyroid carcinoma, and in vitro inhibition of Itch potentiates the effect of chemotherapeutic drugs in a variety of cancer cell lines by enhancing apoptosis in response to drug treatment. We demonstrate that Itch plays a critical role in the in vivo initiation of intestinal adenomas, and ApcMin/+ mice lacking Itch have a 71% reduction in their tumor burden. We hypothesize that epithelial cells lacking Itch (particularly tumor cells) are more sensitive to TXNIP-, p63-, or p73-mediated apoptosis. We will test this hypothesis by 1) determining the role played by Itch in both the epithelium and in the immune system using bone marrow transplantation; 2) delineating the window when ApcMin/+ -derived tumors are sensitive to the loss of Itch using a conditional knockout approach; and 3) characterizing the expression of bona fide Itch targets, Txnip, p63, and p73 in normal vs. tumor vs. 5-fluorouracil treated tissues using Q-PCR, Western blotting, and immunohistochemistry analysis. The data generated herein will provide critical rationale for developing this new potential adjuvant therapy.