2010-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/661318摘要：微RNA是動植物基因表現之負調控因子，參與各種細胞反應且與疾病形成有關，為近年來重要的研究主題。胃癌是全世界所有癌症致死率排名第二，且有較差的預後，因此找出可抑制腫瘤發展是相當重要的。微RNA在許多不同的人類癌症中被證實可作為診斷及預後的生物標誌。研究微RNA在癌症中的表現可提供一個更有效的抗癌治療方法。在我們初步的研究結果中，利用整合性的網路生物學鑑定出微RNA調控的網路，且發現微RNA miR-148a調控的網路對胃癌發展影響是顯著的。此外，我們發現miR-148a在腫瘤組織中的表現減少，其過度表現可減少器官及腹膜的腫瘤入侵而提昇病人的存活率。我們認為miR-148a可能是減緩胃癌惡化的腫瘤抑制基因，因而促使病人具有較佳的預後能力。 本計畫主要目標是要研究微RNA miR-148a在腫瘤抑制上的角色及在胃癌細胞中的調控機制。特定的目標如下： 1. 研究miR-148a在胃癌細胞上抑制腫瘤生長及血管新生的效應，及其細胞凋亡的情形。 2. 探討miR-148a是否對胃癌細胞侵入、遷移及附著能力上具有抑制的影響。 3. 解析miR-148a在網路中所調控的標的基因是否涉及了腫瘤發展。 4. 了解miR-148a在胃癌細胞中的調控分子機制。 本計畫將揭露miR-148a在胃癌形成上所扮演的角色，並了解它在腫瘤抑制中的調控機制，這些資訊將有助於癌症治療。 <br> Abstract: MicroRNAs (miRNAs) are endogenous non-coding small single-stranded RNAs, ~22 nucelotides long, which regulate gene expression at the post-transcriptional level. Interest in miRNAs was further enhanced by studies that revealed the role of miRNAs in many cellular processes, including development, differentiation, proliferation, apoptosis, and stress response, and in various types of disease such as cancer and cardiac diseases. Thus, miRNAs have been a topic of intense research in the past ten years. Gastric cancer is the second leading cause of cancer deaths worldwide and has poor prognosis. The discovery of new targets for tumor progression inhibition is therefore tremendously valuable. miRNAs have been proved as potential biomarkers for diagnosis and prognosis in various human cancers. The investigation of miRNA profiles in cancers for potential therapeutic and prognostic targets may provide a more efficient and effective approach to anticancer therapy. In our previous results, we successfully predicted human miRNAs using tissue-selective motifs in 3` UTRs (Proc. Natl. Acad. Sci. U S A 2008) and found target genes of individual miRNA tend to be hubs and bottlenecks in miRNA regulated protein-protein interaction network (Proteomics 2008). Using integrative network biology, we have identified miRNAs-regulated networks and found that miR-148a belonged to one of the significant networks in gastric cancer. This network is involved in the biological functions, including intergrin-mediated signaling pathway, cell-matrix adhesion, wound healing and blood coagulation. Furthermore, we analyzed miRNA expression profile to identify differentially expressed miRNAs in tumor tissues compared with paired normal tissues. We found that miR-148a expression was reduced in tumor tissues, which was further confirmed by qRT-PCR. In addition, miR-148a overexpression was observed to be associated with clinicopathological factors, including reduced organ and peritoneal invasion, as well as better patient survival. We propose that miR-148a may function as a tumor suppressor associated with better patient prognosis that slows down a more aggressive form of gastric cancer. The major objectives of this proposal are to elucidate the role of miR-148a in tumor suppression and its regulatory mechanism in gastric cancer. The specific aims are: 1. To study the inhibitory effects of miR-148a on tumor growth, angiogenesis and, ultimately, apoptosis in gastric cancer cells. 2. To study whether miR-148a have the suppressive effect on the invasion, migration and adhesion of gastric cancer cells. 3. To study whether the miR-148a-regulated target genes in the network are involved in tumor progression. 4. To understand the regulatory molecular mechanism of miR-148a in gastric cancer cells. With the proposed study, we might be able to elucidate the role of miR-148a on gastric cancer progression and understand more about its regulatory mechanism in tumor suppression. Furthermore, the information will provide a valuable in-depth insight in cancer therapy.微RNA腫瘤抑制網路生物學胃癌調控機制microRNAtumor suppressionnetwork biologygastric cancerregulatory mechanism