Investigating the mechanisms of CD44s splice isoform in breast cancer metastasis
研究CD44s剪接亚型在乳腺癌转移中的机制
基本信息
- 批准号:9312590
- 负责人:
- 金额:$ 30.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-02-04 至 2019-01-31
- 项目状态:已结题
- 来源:
- 关键词:Alternative SplicingAnimalsBindingBreast Cancer CellBreast Cancer PatientBreast Cancer TreatmentBreast cancer metastasisCD44 AntigensCD44 geneCancer EtiologyCell SurvivalCell surfaceCellsCessation of lifeClinicalComplexCouplesCuesDataDevelopmentDevelopmental ProcessEpithelialExclusionExonsFeedbackGenetic TranscriptionGoalsGrowthHealthHumanHyaluronic AcidHyaluronic Acid BindingIGF1R geneLigand BindingMAP Kinase GeneMalignant NeoplasmsMammary NeoplasmsMediatingMembrane MicrodomainsMesenchymalMetastatic breast cancerMolecularNeoplasm MetastasisPathogenesisPatientsPlayProtein FamilyProtein IsoformsRNA SplicingReceptor Protein-Tyrosine KinasesReportingResearchRoleSignal TransductionSpecimenTestingUp-Regulationextracellularin vivomalignant breast neoplasmnovelnovel therapeutic interventionpalmitoylationpromoterreceptorsensorsmall hairpin RNAtranscription factortreatment strategytumor
项目摘要
DESCRIPTION (provided by applicant): Tumor metastasis is the major cause of cancer-related death in most types of human cancers including breast cancer. The long-term goal of our research is to better understand molecular mechanisms of alternative splicing underlying breast cancer metastasis. In this project we propose to investigate the mechanisms of a positive feedback loop involving the CD44s splice isoform and Akt activation that is responsible for breast tumor metastasis. The cell surface molecule CD44 is comprised of a family of proteins that are generated by alternative splicing. Inclusion of different combinations of variable exons generates CD44v. Conversely, exclusion of all of the variable exons produces CD44s. CD44 can be viewed as a sensor for extracellular cues. By forming co-receptor complexes with receptor tyrosine kinases (RTKs) and their growth factors, CD44 augments growth factor-stimulated RTK signaling. Our previous studies showed that CD44v and CD44s act on different signaling cascades: CD44s activates Akt signaling that is critical for promoting cell survival, while CD44v, on the other hand, promotes Ras/MAPK signaling resulting in a cell proliferative state. We recently reported that the CD44s isoform plays an essential role in epithelial-mesenchymal transition (EMT), a developmental process that is abnormally activated in tumor metastasis. We also found that depletion of CD44 by shRNA inhibits breast tumor metastasis in animals and that CD44s expression is upregulated in high-grade patient breast tumor specimens. These results suggest a critical role for CD44s in breast cancer metastasis. Mechanistically, we have shown that CD44s potentiates Akt activation and promotes cell survival. We also found that CD44s-dependent Akt signaling upregulates hyaluronic acid synthase 2 (HAS2) expression. Importantly, the HAS2 product, hyaluronic acid (HA), is a ligand that binds to CD44 and facilitates CD44s- mediated Akt activation. These observations led us to hypothesize that a positive feedback loop couples CD44s and Akt signaling, resulting in sustained Akt activation and promoting breast cancer metastasis. To test our hypothesis we have developed the following specific aims: Aim 1, Determine the molecular mechanism by which CD44s activates Akt signaling. Aim 2, Examine how CD44s-dependent Akt activation promotes HAS2 expression in breast cancer cells. Aim 3, Investigate whether HA, product of HAS2, promotes CD44s-dependent Akt activation and examine the positive-feedback loop in clinical breast tumor metastasis. Successfully accomplishing this project will define a novel mechanism of a positive feedback loop that promotes breast tumor metastasis. Intervening this positive feedback loop could offer an exciting new therapeutic approach for the treatment of metastatic breast cancer.
描述(由申请人提供):在包括乳腺癌在内的大多数人类癌症中,肿瘤转移是癌症相关死亡的主要原因。我们研究的长期目标是更好地了解乳腺癌转移的替代剪接的分子机制。在这个项目中,我们建议研究涉及涉及乳腺肿瘤转移的CD44S剪接同工型和AKT激活的正反馈回路的机制。细胞表面分子CD44由替代剪接产生的蛋白质家族组成。包含可变外显子的不同组合会生成CD44V。相反,排除所有变量外显子都会产生CD44。 CD44可以看作是细胞外提示的传感器。通过与受体酪氨酸激酶(RTK)及其生长因子形成共受体复合物,CD44增强了生长因子刺激的RTK信号传导。我们先前的研究表明,CD44V和CD44对不同的信号级联反应作用:CD44S激活AKT信号,这对于促进细胞存活至关重要,而CD44V则促进RAS/MAPK信号传导导致细胞增殖状态。我们最近报道说,CD44S同工型在上皮 - 间质转变(EMT)中起着至关重要的作用,这是一种在肿瘤转移中被异常激活的发育过程。我们还发现,shRNA耗尽CD44会抑制动物中乳腺肿瘤的转移,并且在高级患者乳腺肿瘤标本中CD44S的表达上调。这些结果表明CD44在乳腺癌转移中起着至关重要的作用。从机械上讲,我们已经表明CD44S增强了Akt激活并促进细胞存活。我们还发现,CD44S依赖性AKT信号传导上调透明质酸合酶2(HAS2)表达。重要的是,HAS2产物透明质酸(HA)是一种与CD44结合并促进CD44S-介导的Akt激活的配体。这些观察结果使我们假设一个正反馈环路CD44和AKT信号传导,从而导致Akt激活并促进乳腺癌转移。为了检验我们的假设,我们开发了以下特定目的:目标1,确定CD44激活AKT信号传导的分子机制。 AIM 2,检查CD44S依赖性AKT激活如何促进乳腺癌细胞中的HAS2表达。 AIM 3,研究HAS2的HA是否促进CD44S依赖性AKT激活,并检查临床乳腺肿瘤转移中的阳性反馈回路。成功完成该项目将定义一种促进乳腺肿瘤转移的正反馈回路的新机制。介入这种积极的反馈循环可以为治疗转移性乳腺癌提供一种令人兴奋的新治疗方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Chonghui Cheng其他文献
Chonghui Cheng的其他文献
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{{ truncateString('Chonghui Cheng', 18)}}的其他基金
Mechanisms of tumor cell clustering in breast cancer metastasis
肿瘤细胞聚集在乳腺癌转移中的机制
- 批准号:
10744976 - 财政年份:2023
- 资助金额:
$ 30.12万 - 项目类别:
Regulation of alternative splicing during epithelial-mesenchymal transition
上皮间质转化过程中选择性剪接的调节
- 批准号:
10594525 - 财政年份:2019
- 资助金额:
$ 30.12万 - 项目类别:
R35 Administrative Supplements for Equipment: Regulation of alternative splicing during epithelial-mesenchymal transition
R35 设备管理补充:上皮-间质转化过程中选择性剪接的调节
- 批准号:
10797795 - 财政年份:2019
- 资助金额:
$ 30.12万 - 项目类别:
Regulation of alternative splicing during epithelial-mesenchymal transition
上皮间质转化过程中选择性剪接的调节
- 批准号:
9901593 - 财政年份:2019
- 资助金额:
$ 30.12万 - 项目类别:
Regulation of alternative splicing during epithelial-mesenchymal transition
上皮间质转化过程中选择性剪接的调节
- 批准号:
10364651 - 财政年份:2019
- 资助金额:
$ 30.12万 - 项目类别:
Regulation of alternative splicing during epithelial-mesenchymal transition
上皮间质转化过程中选择性剪接的调节
- 批准号:
10712743 - 财政年份:2019
- 资助金额:
$ 30.12万 - 项目类别:
R35 Admin Diversity Supplement: Regulation of alternative splicing during epithelial-mesenchymal transition
R35 管理多样性补充:上皮-间质转化过程中选择性剪接的调节
- 批准号:
10720983 - 财政年份:2019
- 资助金额:
$ 30.12万 - 项目类别:
Mechanisms of hnRNPM in Alternative Splicing Regulation During EMT
hnRNPM 在 EMT 期间选择性剪接调控的机制
- 批准号:
8673352 - 财政年份:2014
- 资助金额:
$ 30.12万 - 项目类别:
Investigating the mechanisms of CD44s splice isoform in breast cancer metastasis
研究CD44s剪接亚型在乳腺癌转移中的机制
- 批准号:
9001950 - 财政年份:2014
- 资助金额:
$ 30.12万 - 项目类别:
Investigating the mechanisms of CD44s splice isoform in breast cancer metastasis
研究CD44s剪接亚型在乳腺癌转移中的机制
- 批准号:
8615683 - 财政年份:2014
- 资助金额:
$ 30.12万 - 项目类别:
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