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

描述(申请人提供)：转化生长因子-β是一种多效性细胞因子，在肿瘤发生中既有生长抑制作用，也有生长促进作用。在肿瘤发生的早期阶段，转化生长因子-β作为肿瘤抑制因子发挥作用，但在肿瘤形成的后期，这种抑制作用消失，肿瘤细胞变得更具运动性、侵袭性和更强的抗凋亡能力。目前尚缺乏一个全面的机制来描述转化生长因子-β对肿瘤侵袭和转移的影响。最近的一项研究表明，转化生长因子-β信号转导与microRNA MLR-21的加工增加有关。MIR-21在包括胰腺癌在内的许多实体瘤中过表达，并已被证明抑制了许多抑制侵袭和转移的基因的翻译(如TIMP3、PDCD4、RECK和MASPIN)。本项目通过增加miR-21和miR-181对microRNAs的处理，提出了转化生长因子-β信号在胰腺癌侵袭和转移中的作用。我们的第一个目标是研究转化生长因子-β对胰腺癌细胞miR-21和miR-181加工的影响。目的2研究受体Smads(如Smad2和Smads)的作用，以及抑制Smad7对转化生长因子-β诱导的miRNA加工的影响。目的3重点研究转化生长因子-β/SMAD/miRNA通路在肿瘤侵袭转移中的作用。这将在存在针对miR-21和miR-181的反义或前miR寡核苷酸的情况下使用体外细胞迁移分析进行。最后，我们的第五个目标将试图通过分析在转化生长因子-β刺激的细胞中超过740个微RNA的表达来发现更多受转化生长因子-β信号调节的微RNA。这项研究的成功完成将提供转化生长因子-β信号与细胞侵袭/转移之间的微RNA联系。相关性胰腺癌是最致命的癌症类型之一，约99%是致命性的。更好地了解胰腺癌转移的机制(S)可能会导致改进的治疗方案。从这项研究中获得的数据有助于开发新的治疗靶点来治疗转移性疾病。

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.