A new regulator for Wnt/beta-catenin signaling and prostate tumorigenesis

Wnt/β-连环蛋白信号传导和前列腺肿瘤发生的新调节因子

• 批准号: 9233879
• 负责人: ZIJIE SUN
• 金额: $ 35.27万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-25 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233879
• 关键词: new; regulator; Wnt; beta; catenin

DESCRIPTION (provided by applicant): Accumulated evidence has shown a significant role for the Wnt/?-catenin pathway in prostate development and tumorigenesis. Dysregulation of cytoplasmic and nuclear ?-catenin has been demonstrated to be a key event in tumorigenesis. Thus, the significance of ?-catenin in human tumors was corroborated by discoveries of mutations in both ?-catenin and the destruction complex components in tumor cells. More than 80% of colorectal cancers possess inactive mutations in the tumor suppressor, APC. Mutations in axin were also found in hepatocellular carcinomas. Moreover, point mutations within the four serine/threonine residues in the target sites of GSK32 were found in ?-catenin in a wide variety of human malignancies. Intriguingly, mutations in ?-catenin, APC, and other components of the destruction complex are very rare in prostate cancer samples. However, increased nuclear ?-catenin has been frequently observed in advanced prostate cancers during the disease progression. Therefore, other pathways/mechanisms may play a dominant role in the regulation of the Wnt/??-catenin signaling pathway during the course of prostate cancer initiation and progression. In the past, we identified that LAPSER1, also named LZTS2 (leucine zipper putative tumor suppressor 2), is a novel ?-catenin interacting protein. The human LZTS2 gene is located on chromosome 10q24.3. This region has been shown to be frequently lost in a variety of human tumors, including prostate cancer. Over- expression of LZTS2 protein affects the subcellular localization of ?-catenin, represses the transcriptional activity of ?-catenin, and inhibits cell growth. Intriguingly, a functional HIV Rev-like leucine rich, CRM1/exportin regulated nuclear export signal (NES) was identified within the C-terminus of LZTS2. Through this NES site, LZTS2 can enhance the nuclear export of ?-catenin and reduce the level of nuclear ?-catenin in cells. Using immunohistochemistry approaches, we further demonstrated that LZTS2 is expressed in the cytoplasm of luminal epithelial cells of prostate glands, and its expression is significantly reduced in human prostate tumor samples. These data elucidate an important role for LZTS2 as a novel regulator in Wnt/??-catenin-mediated transcription, cell growth, and tumorigenesis. Although a critical role for the Wnt/??-catenin signaling pathway has been established in prostate tumorigenesis, the precise pathways/mechanisms underlying the dysregulation of??-catenin in prostate cancer cells still remain unclear. Our recent findings that LZTS2 is a ?-catenin interacting protein and modulates the activity and cellular localization of ?-catenin point to LZTS2 as a novel regulator for the Wnt/??-catenin signaling pathway Therefore, we propose a series of experiments in this revised RO1 application to address our central hypothesis that LZTS2 negatively regulates the Wnt/??-catenin signaling pathway and its dysregulation will activate the Wnt/??-catenin signaling pathway and contribute to tumorigenesis. Three specific aims are proposed as follows: 1) characterizing the biological role of LZTS2 using knockout mouse models, 2) examining LZTS2 expression in human prostate cancers, and 3) investigating the dysregulation of Wnt/??-catenin signaling by LZTS2 in prostate tumorigenesis. The above specific aims address the significance of LZTS2 in tumorigenesis and identify the novel mechanisms for dysregulation of Wnt/??-catenin signaling in tumorigenesis. Insights into new diagnostic markers, therapeutic targets and approaches for prostate cancer and other tumors are expected.

描述（由申请人提供）：累积证据表明，在前列腺发育和肿瘤发生中，Wnt/？ - catenin途径发挥了重要作用。细胞质和核？ - 蛋白酶的失调已被证明是肿瘤发生的关键事件。因此，肿瘤细胞中的突变和破坏复合物成分在人类肿瘤中的？ - 蛋白酶在人类肿瘤中的重要性得到了证实。超过80％的结直肠癌在肿瘤抑制剂APC中具有无效的突变。在肝细胞癌中也发现了Axin中的突变。此外，在多种人类恶性肿瘤中发现了GSK32目标部位的四个丝氨酸/苏氨酸残基中的点突变。有趣的是，在前列腺癌样品中，蛋白质，APC和其他破坏复合物的其他成分中的突变非常罕见。但是，在疾病进展过程中，在晚期前列腺癌中经常观察到核能加宁的增加。因此，其他途径/机制在前列腺癌的启动和进展过程中的调节中可能在Wnt/?? - catenin信号通路的调节中起主要作用。 过去，我们确定Lapser1（也称为LZTS2（亮氨酸拉链假定的肿瘤抑制剂2））是一种新颖的？ - 卡宁素相互作用的蛋白质。人LZTS2基因位于10q24.3染色体上。该区域已被证明在包括前列腺癌在内的各种人类肿瘤中经常丢失。 LZTS2蛋白的过度表达会影响 - 蛋白酶的亚细胞定位，抑制？ - 蛋白酶的转录活性，并抑制细胞生长。有趣的是，在LZTS2的C端鉴定了一个功能性HIV Rev样亮氨酸，CRM1/Exportin调节的核输出信号（NES）。通过此NES位点，LZTS2可以增强核出口？ - 蛋白酶的核出口并降低细胞中的核？ - 蛋白质的水平。使用免疫组织化学方法，我们进一步证明了LZTS2在前列腺的腔内上皮细胞的细胞质中表达，其表达在人类前列腺肿瘤样品中显着降低。这些数据阐明了LZTS2作为Wnt/??- catenin介导的转录，细胞生长和肿瘤发生的新调节剂的重要作用。 尽管在前列腺肿瘤发生中已经建立了Wnt/??- catenin信号通路的关键作用，但前列腺癌细胞中catenin失调的确切途径/机制仍然不清楚。我们最近的发现，LZTS2是一种？ - 连续蛋白相互作用，并调节了？ - catenin的活性和细胞定位？ - catenin cot lzts2是Wnt/?? - catenin信号传导途径的新型调节剂，因此，我们提出了在此修订后的RO1中，我们提出了一系列的实验，以解决我们的中心水平，以使我们的中心假设构成lzts 2的范围。失调会激活Wnt/?? - catenin信号通路，并导致肿瘤发生。提出了三个特定目的，如下：1）使用基因敲除小鼠模型表征LZTS2的生物学作用，2）检查人类前列腺癌中的LZTS2表达，3）研究在前列腺肿瘤中通过LZTS2对Wnt/?? catenin信号的失调。以上特定的目的解决了LZTS2在肿瘤发生中的重要性，并确定了肿瘤发生中Wnt/?? - catenin信号传导失调的新型机制。可以洞悉对新的诊断标记，治疗靶标和前列腺癌和其他肿瘤的方法。