SRSF3 Loss and Hepatocellular Carcinoma

SRSF3 缺失与肝细胞癌

基本信息

  • 批准号:
    9205453
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-01-01 至 2019-12-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): RNA splicing is the process of removal of intronic sequences from the primary RNA transcript before the final mRNA is generated. Unlike lower organisms, the vast majority of mammalian genes are spliced. Most genes give rise to multiple mRNAs resulting from differential promoters or termination sequences, or the use of alternative exons. In the broader clinical picture, alternative splicing is an important new area of investigation. Alterations in RNA splicing have now been found in many cancers. As cancer is a leading cause of death among the VA population, understanding how these oncogenic splice variants occur and how they contribute to carcinogenesis is paramount to our understanding of the pathogenesis of the disease and our discovery of novel therapeutic approaches. We have recent data in mice that eliminating a particular RNA splicing factor causes chronic liver damage due to hepatocyte apoptosis and compensatory proliferation. As the mice age, their livers show steatohepatitis and fibrosis, and eventually 100% of the mice succumb to hepatocellular carcinoma (HCC). The loss of the splicing factor does not cause tumors but rather creates a pre-disposition to cancer, similar to a tumor suppressor gene. We believe this model has many parallels to human HCC and can provide great insights into the pathogenesis of this disease that could guide therapeutic development. Based on extensive preliminary data on our splicing factor knockout mouse, we are proposing a comprehensive series of experiments to understand how loss of a single splicing factor in the liver can lead to metastatic hepatocellular carcinoma. These studies will address key questions concerning the fundamental biological process of carcinogenesis and will integrate cell and molecular biological experiments with physiological studies in mice lacking specific splicing factors in liver. We will establish the relevance of this model for human liver cancer by assessing how frequently SRSF3 loss occurs in human HCC, whether loss occurs in all HCC or particular subtypes, and whether loss occurs in early-stage liver disease such as NAFLD, NASH or cirrhosis. In the mouse, loss of SRSF3 predisposes to HCC but not every cell becomes transformed, suggesting that somatic mutations or epigenetic changes must be acquired to produce the carcinoma phenotype. We will attempt to identify these secondary genetic changes by sequencing somatic mutations in the mouse tumors, or assessing changes in CpG methylation in differentially-methylated regions. We will also test whether these genetic changes allow the tumors to become independent of SRSF3 status by restoring SRSF3 expression in the tumor cells. We investigate the molecular mechanisms underlying the aberrant RNA splicing and the associated cellular changes using a combination of CLIP-seq and transcriptome sequencing and splice junction arrays to identify the direct targets for SRSF3 in the hepatocyte. These targets will be tested for SRSF3-dependence using in vitro cultured human hepatoma cells. We will also test a number of SRSF3 mutations have been identified in a variety of cancers including HCC. We will test two potential mechanisms that may contribute to apoptosis, fibrosis, and cell proliferation. We are attempting to connect changes in splicing of the fibronectin and insulin receptor genes with specific intermediate phenotypes, and with tumor growth. These two genes are direct targets for SRSF3 and their splicing is altered in the knockout mouse. We will test whether miss-splicing of the fibronectin gene causes oxidative stress and fibrosis, and whether miss-splicing of the insulin receptor gene allows IGF2 to stimulate tumor cell proliferation and prevent the normal terminal endo-replication of the hepatocyte. These experiments will combine new genetic knockouts with pharmacological stimulation or inhibition of individual pathways. Ultimately, we will test whether these two pathways contribute to hepatocellular carcinogenesis.
 描述(由申请人提供): RNA 剪接是在生成最终 mRNA 之前从初级 RNA 转录物中去除内含子序列的过程。与低等生物不同,绝大多数哺乳动物基因都是剪接的。大多数基因会因差异启动子或终止序列或替代外显子的使用而产生多个 mRNA。从更广泛的临床情况来看,选择性剪接是一个重要的新研究领域。现在在许多癌症中都发现了 RNA 剪接的改变。由于癌症是 VA 人群死亡的主要原因,了解这些致癌剪接变异如何发生以及它们如何促进致癌作用对于我们了解该疾病的发病机制和发现新的治疗方法至关重要。 我们最近在小鼠中获得的数据表明,消除特定的 RNA 剪接因子会因肝细胞凋亡和代偿性增殖而导致慢性肝损伤。随着小鼠年龄的增长,它们的肝脏出现脂肪性肝炎和纤维化,最终100%的小鼠死于肝细胞癌(HCC)。剪接因子的丢失不会导致肿瘤,而是会产生癌症倾向,类似于肿瘤抑制基因。我们相信该模型与人类肝癌有许多相似之处,可以为这种疾病的发病机制提供深入的见解,从而指导治疗的发展。 基于我们剪接因子敲除小鼠的大量初步数据,我们提出了一系列全面的实验,以了解肝脏中单个剪接因子的缺失如何导致转移性肝细胞癌。这些研究将解决有关致癌的基本生物学过程的关键问题,并将细胞和分子生物学实验与肝脏缺乏特定剪接因子的小鼠的生理研究相结合。 我们将通过评估人类 HCC 中 SRSF3 丢失的频率、丢失是否发生在所有 HCC 或特定亚型中,以及丢失是否发生在早期肝病(如 NAFLD、NASH 或肝硬化)中,来建立该模型与人类肝癌的相关性。在小鼠中,SRSF3 的缺失易患 HCC,但并非每个细胞都会发生转化,这表明必须获得体细胞突变或表观遗传变化才能产生癌症表型。我们将尝试通过对小鼠肿瘤中的体细胞突变进行测序,或评估差异甲基化区域中 CpG 甲基化的变化来识别这些继发性遗传变化。我们还将测试这些基因变化是否可以通过恢复肿瘤细胞中的 SRSF3 表达来使肿瘤变得独立于 SRSF3 状态。 我们结合使用 CLIP-seq 和转录组测序以及剪接点阵列来研究异常 RNA 剪接和相关细胞变化的分子机制,以确定肝细胞中 SRSF3 的直接靶标。将使用体外培养的人肝癌细胞测试这些靶标的 SRSF3 依赖性。我们还将测试在包括 HCC 在内的多种癌症中已发现的一些 SRSF3 突变。 我们将测试可能导致细胞凋亡、纤维化和细胞增殖的两种潜在机制。我们正在尝试连接拼接的变化 纤连蛋白和胰岛素受体基因具有特定的中间表型,并且与肿瘤生长有关。这两个基因是 SRSF3 的直接靶标,它们的剪接在敲除小鼠中发生了改变。我们将测试纤连蛋白基因的错误剪接是否会导致氧化应激和纤维化,以及胰岛素受体基因的错误剪接是否会使IGF2刺激肿瘤细胞增殖并阻止肝细胞正常的末端内复制。这些实验将把新的基因敲除与单个途径的药理刺激或抑制结合起来。最终,我们将测试这两种途径是否有助于肝细胞癌变。

项目成果

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NICHOLAS J WEBSTER其他文献

NICHOLAS J WEBSTER的其他文献

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{{ truncateString('NICHOLAS J WEBSTER', 18)}}的其他基金

ShEEP Request for MESO SECTOR S 600MM Ultra-Sensitive Plate Imager
ShEEP 请求 MESO SECTOR S 600MM 超灵敏板成像仪
  • 批准号:
    10741205
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
SRSF3 degradation in liver disease and hepatocellular carcinoma
肝脏疾病和肝细胞癌中的 SRSF3 降解
  • 批准号:
    10162302
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
SRSF3 degradation in liver disease and hepatocellular carcinoma
肝脏疾病和肝细胞癌中的 SRSF3 降解
  • 批准号:
    10618856
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
BLR&D Research Career Scientist Award Application
BLR
  • 批准号:
    10454119
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
SRSF3 degradation in liver disease and hepatocellular carcinoma
肝脏疾病和肝细胞癌中的 SRSF3 降解
  • 批准号:
    10002586
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
BLR&D Research Career Scientist Award Application
BLR
  • 批准号:
    10219156
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
SRSF3 degradation in liver disease and hepatocellular carcinoma
肝脏疾病和肝细胞癌中的 SRSF3 降解
  • 批准号:
    10454816
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
BLR&D Research Career Scientist Award Application
BLR
  • 批准号:
    10618230
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Time-Restricted Feeding and Breast Cancer
限时喂养与乳腺癌
  • 批准号:
    9882965
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Time-restricted feeding and breast cancer
限时喂养与乳腺癌
  • 批准号:
    10462993
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:

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