| 摘要: | 微型RNA (MicroRNAs or miRNAs) 已有利用微型RNA模擬物或抑制物，來干擾失調的訊息傳導路徑，在臨床測試中來達到治療疾病的目的。Ｍitogen-activated protein kinase (MAPK/ERK) signaling 的過度活化與許多細胞癌化息息相關，例如黑色素癌。先前我們利用microRNA晶片實驗去篩選可能參與MAPK路徑的微型RNA。經分析後，篩選出與MAPK路徑有顯著關係的二十二個微型RNA。之前計劃中已完成其中miR-524-5p與另一微型RNA miR-596在抑制黑色素癌及其在影響的機制的研究並成果已發表，並被review收錄我們的結果。另外，我們建立在二株BRAF 抑制劑抗藥性的黑色素癌細胞株，結果顯示miR-524-5p可以在細胞及動物實驗上均抑制PLX4032抗藥性的黑色素癌的增殖並在檢體中不僅miR-524-5p的表現可以區分良性痣及黑色素癌，並且更重要是對病人BRAF 抑制劑的反應有顯著相關，此結果正要投搞中。我們會藉由這項優勢來繼續系統性的探討MAPK路徑有顯著關係的微型RNA。在這個研究計畫，主要目標繼續了解其他MAPK路徑有顯著關係的微型RNA在黑色素癌及對標靶藥BRAF 抑制劑抗藥性的黑色素癌的效果，並進一步想要解析BRAF 抑制劑治療後，黑色素瘤細胞會如何釋放因子在腫瘤的微環境中，影響抗藥性和第二癌症的產生。深入探討MAPK路徑相關的微型RNA，是否會負調控其機制影響腫瘤微環境並且可為一個偵測或預後的生物標記做詳細的探索。此研究計畫的新發現，將可以闡明新一層微型RNA在黑色素瘤及其微環境的影響及機制。此外，此研究新知識，有潛力可應用於發展新的診斷方法或對疾病的治療，並可以增進基礎和轉譯醫學的研究。 ;The mitogen-activated protein kinase (MAPK/ERK) signaling occupies an essential role in many cancer progressions, including melanoma. BRAF is mutated frequently in melanoma (~60-80%) and this causes MAPK/ERK signaling activation. BRAF inhibitors such as PLX4032 (Vemurafenib) have improved overall survival in BRAF mutant melanoma patients, but the most patients will develop drug resistance within an average 7 months via reactivation of MAPK/ERK and alternative pathways. Notably, the activity of MAPK/ERK signaling can be modulated by microRNA (miRNAs) derived from tumor microenvironment through extracellular vesicles. As consequence, these miRNAs contribute significantly to therapy responses. Our previous efforts had led to identify 22 miRNAs associated with MAPK/ERK pathway. Most importantly, our studies demonstrated that miR-524-5p and miR-596 regulate MAPK/ERK signaling to suppress melanoma (Liu et al., Journal of Investigative Dermatology, 2018 and Oncotarget, 2014). Consistent with this premise, miR-524-5p overexpression led to reduce the development of PLX4032-resistant melanoma in vitro and in vivo through MAPK/ERK and PI3K/AKT signaling pathways. Interestingly, miR-524-5p level was higher in complete response compared partial response patients treated with BRAF inhibitors (Nguyen MH et al., To be submitted). The significance of our work has been specifically recognized and mentioned in a review article by a leading scientist in the field (Masliah-Planchon, 2016). Given that the advantage of being the leading position in this subject, we will systematically delineate how these 22 miRNAs functionally interact with MAPK/ERK pathway. Specifically, we will evaluate whether these candidate miRNAs have the therapeutic effects for melanoma, and BRAF inhibitor-induced resistance and second tumorigenesis. Most importantly, the possible roles of tumor microenvironment in this regard will be investigated. For example, how these miRNAs influence the tumor microenvironment mechanistically. The ultimate goal of this proposal is to decipher the molecular network of candidate miRNAs in MAPK/ERK signaling; and hopefully, the knowledge we gain from this study can potentially be extended in the discovery of new prognosis or therapy targets for diseases. |
