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）：积累的证据表明Wnt/β-连环蛋白途径在前列腺发育和肿瘤发生中具有重要作用。细胞质和核β-连环蛋白的失调已被证明是肿瘤发生的关键事件。因此，β-连环蛋白在人类肿瘤中的重要性通过肿瘤细胞中β-连环蛋白和破坏复合物成分的突变的发现得到证实。超过 80% 的结直肠癌具有抑癌基因 APC 的非活性突变。肝细胞癌中也发现了轴蛋白突变。此外，在多种人类恶性肿瘤的β-连环蛋白中发现了GSK32靶位点的四个丝氨酸/苏氨酸残基内的点突变。有趣的是，β-连环蛋白、APC 和破坏复合物的其他成分的突变在前列腺癌样本中非常罕见。然而，在疾病进展过程中，晚期前列腺癌中经常观察到核β-连环蛋白增加。因此，在前列腺癌的发生和进展过程中，其他途径/机制可能在Wnt/β-catenin信号通路的调节中发挥主导作用。 过去，我们发现 LAPSER1，也称为 LZTS2（亮氨酸拉链推定肿瘤抑制因子 2），是一种新型的 β-连环蛋白相互作用蛋白。人类LZTS2基因位于染色体10q24.3上。该区域已被证明在多种人类肿瘤中经常丢失，包括前列腺癌。 LZTS2蛋白的过度表达影响β-连环蛋白的亚细胞定位，抑制β-连环蛋白的转录活性，并抑制细胞生长。有趣的是，在 LZTS2 的 C 末端发现了一个功能性的 HIV Rev 样富含亮氨酸、CRM1/exportin 调节的核输出信号 (NES)。通过该NES位点，LZTS2可以增强β-连环蛋白的核输出并降低细胞内的核β-连环蛋白水平。利用免疫组织化学方法，我们进一步证明LZTS2在前列腺管腔上皮细胞的细胞质中表达，并且其表达在人前列腺肿瘤样本中显着降低。这些数据阐明了 LZTS2 作为 Wnt/β-连环蛋白介导的转录、细胞生长和肿瘤发生中的新型调节剂的重要作用。 尽管Wnt/β-连环蛋白信号通路在前列腺肿瘤发生中的关键作用已被确定，但前列腺癌细胞中β-连环蛋白失调的精确通路/机制仍不清楚。我们最近发现 LZTS2 是一种 β-catenin 相互作用蛋白，可调节 β-catenin 的活性和细胞定位，表明 LZTS2 作为 Wnt/β-catenin 信号通路的新型调节因子。因此，我们在此提出了一系列实验。修改了 RO1 应用程序，以解决我们的中心假设，即 LZTS2 负向调节 Wnt/β-catenin 信号通路，其失调将激活 Wnt/β-catenin 信号通路并促进肿瘤发生。提出了三个具体目标如下：1）使用敲除小鼠模型表征 LZTS2 的生物学作用，2）检查人类前列腺癌中的 LZTS2 表达，以及 3）研究 LZTS2 在前列腺肿瘤发生中对 Wnt/β-catenin 信号传导的失调。上述具体目标阐述了 LZTS2 在肿瘤发生中的重要性，并确定了肿瘤发生中 Wnt/β-连环蛋白信号传导失调的新机制。期望深入了解前列腺癌和其他肿瘤的新诊断标志物、治疗靶点和方法。