TGF-Beta signaling and microRNA processing: Implications for invasion and metasta

TGF-Beta 信号传导和 microRNA 处理：对侵袭和转移的影响

• 批准号: 8323105
• 负责人: Ana Clara Pereira Azevedo-Pouly
• 金额: $ 3.62万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323105
• 关键词: Affect; Aftercare; Apoptosis; BMP4; Biological Assay; Blood Vessels; Cells; Cellular Morphology; Complex; Data; Development; Disease; Epithelial; Family; Genes; Goals; Growth; Immigration; In Vitro; Lead; Link; Luciferases; MADH2 gene; MADH7 gene; Malignant neoplasm of pancreas; Mesenchymal; MicroRNAs; Microprocessor; Migration Assay; Molecular Profiling; Neoplasm Metastasis; Neoplasms; Oligonucleotides; Oncogenic; Pancreatic Adenocarcinoma; Pathway interactions; Process; RNASE3L gene; Regulation; Reporter; Resistance; Role; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Solid Neoplasm; Staging; TGF Beta Signaling Pathway; TIMP3 gene; Testing; Time; Transforming Growth Factor beta; Translations; Tumor Suppressor Proteins; base; cancer type; cell motility; cytokine; defined contribution; improved; inhibitor/antagonist; knock-down; maspin; migration; neoplastic cell; new therapeutic target; pancreatic cancer cells; pre-miRNA; pri-miRNA; public health relevance; receptor; research study; tumor; tumorigenesis

DESCRIPTION (provided by applicant): TGF-beta is a pleiotropic cytokine that has both growth suppressive and growth promoting activates in oncogenesis. During the early stages of tumorigenesis TGF-beta acts as a tumor suppressor, however at later stages of neoplasia, this tumor suppressive role is lost and tumor cells become more motile, more invasive and more resistant to apoptosis. A comprehensive mechanism to describe the effects that TGF-beta has on invasion and metastasis is lacking. A recent study has shown that TGF-beta signaling is responsible for increased processing of the microRNA mlR-21. miR-21 is over expressed in a number of solid tumors including pancreatic cancer and has been shown to suppress the translation of a number of genes that inhibit invasion and metastasis (e.g. TIMP3, PDCD4, RECK and maspin). This project proposes a role for TGF-beta signaling in invasion and metastasis of pancreatic cancer through the increased processing of microRNAs miR-21 and miR-181. Our first aim will study the effects of TGF-beta on the processing of miR-21 and miR-181 in pancreatic cancer cells. Aim 2 will investigate the role of the receptor SMADs (e.g. SMAD2 and SMADS) and the inhibitory SMAD7 on TGF-beta induced miRNA processing will be investigated. Aim 3 focuses on defining the contribution of the TGF-beta/SMAD/miRNA pathway on invasion and metastasis. This will be carried out using in vitro cell migration assays in the presence of antisense or pre-miR oligonucleotides to miR- 21 and miR-181. Finally, our fifth aim will attempt to discover additional microRNAs that are regulated by TGF-beta signaling by profiling the expression of over 740 microRNAs in cells stimulated with TGF-beta. Successful completion of this study will provide a microRNA link between TGF-beta signaling and cell invasion/metastasis. Relevance Pancreatic adenocarcinoma is one of the most lethal types of cancer and is approximately 99% fatal. Better understanding of the mechanism(s) responsible for pancreatic cancer metastasis could lead to improved treatment options. Data acquired from this study my lead to the development of new therapeutic targets to treat metastatic disease.

描述（由申请人提供）：TGF-β是一种多效性细胞因子，在肿瘤发生中具有生长抑制和生长促进活性。在肿瘤发生的早期阶段，TGF-β充当肿瘤抑制因子，但在肿瘤形成的后期阶段，这种肿瘤抑制作用消失，肿瘤细胞变得更活跃、更具侵袭性并且更能抵抗细胞凋亡。缺乏全面的机制来描述 TGF-β 对侵袭和转移的影响。最近的一项研究表明，TGF-β 信号传导负责增强 microRNA mlR-21 的加工。 miR-21 在包括胰腺癌在内的许多实体瘤中过度表达，并已被证明可以抑制许多抑制侵袭和转移的基因（例如 TIMP3、PDCD4、RECK 和 maspin）的翻译。该项目提出 TGF-β 信号传导通过增强 microRNA miR-21 和 miR-181 的加工在胰腺癌的侵袭和转移中发挥作用。我们的第一个目标是研究 TGF-β 对胰腺癌细胞中 miR-21 和 miR-181 加工的影响。目标 2 将研究受体 SMAD（例如 SMAD2 和 SMADS）的作用，并研究抑制 SMAD7 对 TGF-β 诱导的 miRNA 加工的作用。目标 3 侧重于定义 TGF-β/SMAD/miRNA 通路对侵袭和转移的贡献。这将在 miR-21 和 miR-181 的反义或前 miR 寡核苷酸存在下使用体外细胞迁移测定进行。最后，我们的第五个目标是通过分析 TGF-β 刺激的细胞中超过 740 个 microRNA 的表达情况，尝试发现其他受 TGF-β 信号调节的 microRNA。这项研究的成功完成将提供 TGF-β 信号传导与细胞侵袭/转移之间的 microRNA 联系。相关性 胰腺癌是最致命的癌症类型之一，死亡率约为 99%。更好地了解胰腺癌转移的机制可能会导致治疗方案的改进。从这项研究中获得的数据有助于开发治疗转移性疾病的新治疗靶点。

项目成果

miR-216 and miR-217 expression is reduced in transgenic mouse models of pancreatic adenocarcinoma, knockout of miR-216/miR-217 host gene is embryonic lethal.

• DOI: 10.1007/s10142-016-0512-1
• 发表时间: 2017-05
• 期刊: Functional & integrative genomics
• 影响因子: 2.9
• 作者: Azevedo-Pouly AC;Sutaria DS;Jiang J;Elgamal OA;Amari F;Allard D;Grippo PJ;Coppola V;Schmittgen TD
• 通讯作者: Schmittgen TD