2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647233摘要：肺癌（尤其是非小細胞肺癌）是國人及全世界癌症死亡率的第一名。延遲診斷和早期轉移是目前治療肺癌主要未解決的困難及障礙，故深入瞭解造成肺癌病變以及轉移的特殊分子機制有助新療法的發展。miRNAs 是小片段且non-coding的單股內生性RNA，藉由類似RNAi的方式抑制並調控下游基因的表現進而影響細胞增生、發育以及凋亡。近期研究發現特定miRNAs能作為抑癌基因或是致癌基因，因其表現量的改變會間接造成下游基因群的表現變異，使得細胞產生病變進而惡性癌化。利用miRNAs微陣列晶片，我們發現miR-135b的表現與癌症細胞轉移能力有高度相關性，且其在非小細胞肺癌病人中的表現量與病人存活率成反比。大量表現miR-135b 會促進肺癌細胞的移動以及侵犯能力;若抑制miR-135b則能降低肺癌細胞的移動以及侵犯能力。初步預測並實驗顯示抑癌基因LZTS1可能是miR-135b所調控的標的基因群之一。而LZTS1在肺腺癌病人中的蛋白質表現量與病人的存活率是成正相關。然而miR-135b調控癌症的詳細分子機制仍有待釐清，其在肺癌細胞中所執行的功能以及造成miR-135b表現異常的原因都需進一步探討分析。我們也將探討miR-135b以及其調控的下游基因是否能作為預測肺癌癒後的生物指標，並利用動物實驗研究antagomiR以及sponge等miR-135b抑制劑對於肺癌的惡化是否具有療效。此計畫將深入探討上述問題，並將研究成果作為臨床轉譯的依據。在本計畫中，預計完成四個具體目標：1. 利用體外與體內模式實驗以及臨床病人檢體的檢測以證實miR-135b/Lzts-1的作用機制在肺癌病程中所扮演的致癌角色。2. 分析miR-135b的作用標的基因, 同時探討這些標的基因在肺癌病程所扮演的功能性角色。3. 探討調控miR-135b表現的作用機轉。4. 開發可抑制miR-135b的antagomiR或是sponge, 以做為新的肺癌治療策略。<br> Abstract: Lung cancer, predominantly the non-small-cell lung cancer (NSCLC) cell type, is the leading cause of cancer mortality worldwide as well as in Taiwan. Delayed diagnosis and early metastasis are the major unsolved obstacles for most physicians in treating lung cancer patients. Understanding the specific driving mechanism involved in lung cancer progression and metastasis will benefit for new therapeutic development. The microRNAs (miRNAs) are new class of small non-protein-coding RNAs that can act as endogenous RNA interference. Recent evidence indicates that miRNAs may function as tumor suppressors or oncogenes, and alteration in miRNA expression may play a critical role in the tumorigenesis and cancer progression.We recently identified a putative oncomiR, miR-135b, which may promote lung cancer progression. The expression of miR-135b was negatively correlated overall survival of NSCLC patients. Overexpression of miR-135b promoted lung cancer migration, invasion and lung tumor growth, while knockdown of miR-135b suppressed that. Preliminary results of target gene prediction identified that the tumor suppressor LZTS1 might be one of the potential targets. The expression of miR-135b was inversely associated with LZTS1 expression in lung adenocarcinoma. However, the detailed mechanism how miR-135b modulates its downstream target genes expression and exert its oncogenic function in promoting lung cancer progression and how miR-135b is regulated are still unknown. In this proposed project, we are aiming to in depth investigate the oncogenic mechanisms of miR-135b, identify its target genes and characterize their functions. We will also try to dissect the mechanisms how the miR135b was regulated. Finally, we will translate this research result for potential clinical application. More specifically, we will investigate whether the miR-135b and its target genes can serve as biomarkers to predict NSCLC outcome. We will elucidate the significance of this oncogenic pathway (miR-135b-LZTS1 and other target genes) involved in lung cancer progression. We will also explore whether the miR-135b antagomiR or miR sponge can serve as a therapeutic option to suppress NSCLC progression and metastasis through inhibition of this oncogenic pathway. To fulfill the proposal, four aims are proposed here:Specific Aims1. To confirm the oncogenic role the miR-135b/LZTS1 pathway plays in lung cancer progression in clinical tumor samples as well as in the in vitro and in vivo models.2. To identify the miR-135b target genes and characterize their functions involved in lung cancer progression.3. To investigate the control and regulatory mechanisms of miR-135b expression.4. To develop the miR-135b antagomiR or sponge as a new therapeutic strategy to suppress lung cancer progression.肺癌致癌基因微陣列晶片non-small-cell lung cancermiR-135bLZTS1