Clinical Significance of Pancreatic Cancer Differentiation and Dedifferentiation

胰腺癌分化和去分化的临床意义

• 批准号: 9538162
• 负责人: Huamin Wang
• 金额: $ 11.46万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9538162
• 关键词: Area; Attenuated; Automobile Driving; Cancer Biology; Collection; Consequentialism; Data; Disease; Disease Outcome; Down-Regulation; Epigenetic Process; Gene Expression; Genetic; Goals; Hypermethylation; Intervention; Investigation; Lead; Link; Malignant neoplasm of pancreas; Mediating; Modality; Molecular; Molecular Genetics; Molecular Target; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Phenotype; Premalignant; Preventive; Regulation; Research; Resources; Role; Signal Pathway; Signal Transduction; Specimen; Testing; Therapeutic; Therapeutic Intervention; Translations; Validation; clinical material; clinically relevant; clinically significant; design; effective intervention; mouse model; novel; overexpression; public health relevance; restoration; transcription factor; tumor; tumor progression

 DESCRIPTION (provided by applicant): Invasive pancreatic cancer (PDA) is a lethal disease. While certain genetic and epigenetic alterations have been well known for years, to date this has not resulted in useful preventive and/or therapeutic modalities. Our research goal is to identify driving alterations in gene expression that can be utilized to develop effective strategie to control PDA differentiation and progression. Our previous studies have demonstrated that transcription factor KLF4 is drastically decreased in invasive PDA and this dysregulation critically promotes PDA biology, whereas PanINs do not exhibit substantially reduced KLF4 expression. In sharp contrast, our recent study has shown a consistent miR-152 underexpression/DNMT1 overexpression in invasive PDA as compared to that in PanINs. Causally linking miR-152-DNMT1-KLF4 pathway to PDA differentiation/dedifferentiation is highly significant in understanding PDA progression. We postulate that downregulation of miR-152 expression causes DNMT1 overexpression and KLF4 downregulation and consequential acquisition of de-differentiated phenotype in PDA, i.e., a switch from PanINs to invasive PDA. Therefore, activation and/or restoration of miR-152 signaling could attenuate PanINs progression. To test our hypothesis, we propose three specific aims: (1) To determine the clinical significance of PDA differentiation and its regulation by KLF4 hypermethylation; (2) To determine the causal role of DNMT1 in PDA differentiation and potential mechanisms underlying its dysregulation; and (3) Determine the utility of targeting miR-152-DNMT1-KLF4 signaling pathway for therapeutic intervention of PDA. These three novel specific aims with clinical relevant questions, mechanistic substantiation using clinical materials and translational validation, are supported by our respective preliminary data and can be tested independently using our unique research resources, yet they are highly interrelated and support one another. Our proposed studies will take advantage of the unique resources available at MD Anderson, including our large collection of PDA specimens and mouse models. Given the important role of miR-152/DNMT1/KLF4 we will uncover, we predict that completion of these studies will provide insightful information for the molecular genetic basis of PDA progression and for identification of molecular targets to design effective intervention strategies. In the long term, our study also ca lead to further investigation of the molecular mechanisms mediating dysregulation of this novel miR-152/DNMT1/KLF4 signaling pathway, and potential translation or our findings into developing effective preventive and therapeutic strategies to control PDA progression.

 描述（由申请人提供）：侵袭性胰腺癌（PDA）是一种致死性疾病。虽然某些遗传和表观遗传改变多年来已为人们所熟知，但迄今为止，这尚未导致有用的预防和/或治疗方式。我们的研究目标是确定基因表达的驱动改变，可以用来开发有效的策略来控制PDA的分化和进展。 我们以前的研究表明，转录因子KLF 4在侵袭性PDA中急剧减少，这种失调严重促进PDA生物学，而PanIN并没有表现出显著减少的KLF 4表达。与此形成鲜明对比的是，我们最近的研究表明，与PanIN相比，侵袭性PDA中的miR-152低表达/DNMT 1过表达一致。将miR-152-DNMT 1-KLF 4途径与PDA分化/去分化联系起来对于理解PDA进展具有高度意义。 我们推测miR-152表达的下调导致DNMT 1过表达和KLF 4下调，从而导致PDA中去分化表型的获得，即，从PanIN转向侵入性PDA。因此，miR-152信号传导的激活和/或恢复可以减弱PanIN的进展。为了验证我们的假设，我们提出了三个具体目标：（1）确定PDA分化及其通过KLF 4超甲基化调节的临床意义;（2）确定DNMT 1在PDA分化中的因果作用及其失调的潜在机制;（3）确定靶向miR-152-DNMT 1-KLF 4信号通路对PDA治疗干预的效用。 这三个新的具体目标与临床相关问题，使用临床材料和翻译验证的机制证实，由我们各自的初步数据支持，可以使用我们独特的研究资源进行独立测试，但它们高度相关，相互支持。我们提出的研究将利用MD安德森的独特资源，包括我们大量的PDA标本和小鼠模型。 鉴于我们将发现miR-152/DNMT 1/KLF 4的重要作用，我们预测这些研究的完成将为PDA进展的分子遗传学基础和鉴定 分子靶点设计有效的干预策略。 从长远来看，我们的研究还可以进一步研究介导这种新的miR-152/DNMT 1/KLF 4信号通路失调的分子机制，并将我们的发现转化为开发有效的预防和治疗策略以控制PDA进展。