Abstract
摘要:癌幹細胞被定義為一群具有自我複製能力且具有異質性的腫瘤細胞。最近有些研究顯示人類胃腫瘤中也有癌幹細胞的存在;胃癌在全世界所有癌症致死率排名第二。由於癌幹細胞比其他癌細胞更具有抗藥性,所以研究癌幹細胞將有助於發展新穎抗癌方法。微型核醣核酸(miRNA)是可降解其標地基因之mRNA或抑制其蛋白質表現之後轉錄負調控因子。單一miRNA可以引發一連串反應並影響其他miRNA或mRNA的回饋路徑。miRNA調控失調會造成細胞增生、分化、存活或轉移;在癌細胞中miRNA調控重要的分子網路。單一基因標靶不能有效地治療癌症,以miRNA調控的分子網路為治療標靶,將可提供一個更有效的抗癌方法。
本計畫的主要目標為整合胃癌幹細胞的各種高通量體學資料,找出重要的miRNA和它們在胃癌進程中的調控網路,進而應用於癌症診斷治療上。
特定目標如下:
1. 建立胃癌幹細胞模式。
2. 解析在胃癌進程中重要的miRNAs。
3. 揭露在胃癌進程中的轉錄體和降解體。
4. 分析在胃癌進程中的蛋白體。
5. 藉由整合miRNAs、轉錄體、降解體及蛋白體資料,闡明miRNA標地基因及了解在胃癌進程中其調控網路和分子機制。
6. 應用於其它癌症的診斷及治療。
本計畫將探討miRNA及其目標基因和網路在胃癌形成上所扮演的角色及調控機制,這些資訊將有助於癌症診斷及治療。
Abstract: Cancer stem cells (CSCs) have been defined as the tumor cells that possess the capability for self-renewal and that can cause the heterogeneous lineages of cancer cells constituting the tumor. John E. Dick first demonstrated the existence of CSCs in human acute myeloid leukemia more than a decade ago. Recent findings also support the existence of gastric CSCs in the human gastric tumors. Gastric cancer is the fourth common cancer and the second highest cause of cancer-related mortality after lung cancer. CSCs seem to be generally more resistant than other cancer cells to conventional anticancer therapeutics. The CSCs expanding research may facilitate the development of novel therapies for the treatment of human cancer.
MicroRNAs (miRNAs) are a class of endogenous, small and highly conserved noncoding RNAs that control gene expression post-transcriptionally, either by degradation of target mRNAs or by inhibition of protein translation. They play critical roles in many cellular processes, including development, differentiation, proliferation, apoptosis, and stress response, and in various types of diseases such as cancer and cardiac diseases. A single miRNA can provoke a chain reaction and feedback pathways involving multiple miRNAs and affecting multiple target genes of the same or different pathways. miRNAs also regulate critical molecular networks in cancer. Single-gene target is not efficient for cancer treatment; therefore, discovering molecular networks regulated by cancer-related miRNAs could be exploited for the design of new treatments.
The major objectives of this proposal are to find out the crucial miRNAs and their regulatory networks in gastric cancer progression by integrating high-throughput omics data of gastric cancer stem cells; then to apply for cancer therapy.
The specific aims are:
1. To establish a gastric cancer stem cell model.
2. To profile miRNAs in gastric cancer progression using small RNA sequencing.
3. To explore transcriptomes and degradomes in gastric cancer progression using RNA sequencing.
4. To analyze proteomes in gastric cancer progression using isobaric tags for relative and absolute quantization (iTRAQ) technique.
5. To reveal the targets of miRNAs as well as to understand the regulatory networks and molecular mechanism of miRNAs in gastric cancer progression by integrating miRNA profile, transcriptome, degradome and proteome.
6. To validate the potential miRNA therapeutic and prognostic targets in gastric cancer clinical specimens and apply them to other cancer types.
With the proposed study, we might be able to elucidate the roles of miRNAs and understand their regulatory mechanism on gastric cancer progression. Furthermore, the information will provide a valuable in-depth insight in cancer therapy.
Keyword(s)
癌幹細胞
微型核醣核酸
網路生物學
胃癌
體學
Cancer stem cell
MicroRNA
Network biology
Gastric cancer
Omics