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

描述（由申请人提供）：tgf - β是一种多效细胞因子，在肿瘤发生中具有抑制生长和促进生长的活性。在肿瘤发生的早期阶段，tgf - β作为肿瘤抑制因子，然而在肿瘤形成的后期阶段，这种肿瘤抑制作用丧失，肿瘤细胞变得更具运动性，更具侵袭性，更耐凋亡。目前还缺乏描述tgf - β在侵袭和转移中的作用的综合机制。最近的一项研究表明，tgf - β信号是导致microRNA mlR-21加工增加的原因。miR-21在包括胰腺癌在内的许多实体肿瘤中过表达，并且已被证明可以抑制一些抑制侵袭和转移的基因的翻译（例如TIMP3， PDCD4， RECK和maspin）。本项目提出tgf - β信号通过增加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。目的2将研究受体SMADs（例如SMAD2和SMADs）的作用，并研究SMAD7对tgf - β诱导的miRNA加工的抑制作用。目的3侧重于确定tgf - β /SMAD/miRNA通路在侵袭和转移中的作用。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试验进行。最后，我们的第五个目标将通过分析tgf - β刺激细胞中超过740种microrna的表达，试图发现受tgf - β信号调节的其他microrna。这项研究的成功完成将提供tgf - β信号与细胞侵袭/转移之间的microRNA联系。胰腺癌是最致命的癌症之一，致死率约为99%。更好地了解胰腺癌转移的机制可以改善治疗方案。从这项研究中获得的数据导致了治疗转移性疾病的新治疗靶点的开发。

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.