摘要:乳癌屬於一種包含多種形態、生物反應、生物行為以及對治療的反應都不盡相同的異質性疾病。其中,乳癌當中的一種亞型-三陰性乳癌在臨床通常具有較高的侵略行為,並且目前亦缺乏有效的標靶治療方向。癌細胞轉移佔三陰性乳癌導致的病人死亡率的百分之九十以上。因此,如何有效預防腫瘤轉移,已成為一個重要研究方向。轉移是分為多步驟的一個複雜過程,在這當中乳癌細胞侵入鄰近的組織,通透過血管,並且滲出到周圍組織,最後擴散到其他地區並且在該處形成另外一個腫瘤。最近,被證實具有RNA 干擾作用的microRNA,被發現參與在調控多種細胞發育,甚至人類疾病發病的過程中。證據顯示,miRNA 和癌症的發生和發展有密切的關聯性,在某些人類癌症,如肝癌,乳腺癌,肺癌,前列腺癌都有特殊miRNA 的表現。但是,這些特殊表現的miRNA 所具有的功能、具體步驟以及對於癌細胞惡性度的變化和轉移所造成的影響仍然不清楚。最近,透過基因篩選的研究確立miRNA 對於癌細胞的轉移確實會有影響。證據顯示,相較於正常乳腺組織,乳癌組織中miRNA 的表現量是異常的。當癌細胞需要進行轉移或侵犯鄰近組織時,miRNA 可能會透過調控細胞內的生物變化來達到前述目標。這種可以聯合多種基因進行細胞調控作用的特性,讓我們可以大膽假設某些miRNA 可能對於乳癌細胞的轉移扮演重要的調節性角色。此外,最近的研究顯示,miRNA 會受到微環境變化的影響(如缺氧或壓力)。利用表現基因體學說解釋miRNA的表現認為這樣的調節似乎透過DNA 甲基化和組蛋白的修飾作用,但詳細的機轉到目前仍不清楚。基於上述這些原因,我們有極大的研究興趣在於探討相關miRNA 和basal-like 乳癌轉移的關聯性,本研究可以提供並且解釋miRNAs 參與在癌細胞轉移過程當中扮演的角色以及其相關的下游基因的關聯性為何。更具體地說,本子計畫的研究目標在於:(1)確定和basal-like subtype 乳癌細胞轉移有關的miRNA有哪些。(2)確定前述miRNA 之下游基因為何。(3)確認miRNA 調節細胞轉移的路徑和步驟。(4)釐清缺氧和腫瘤轉移的關聯性(5)驗證臨床病人腫瘤內miRNA 表達量變化結果是否相符
Abstract: Breast cancer comprises a heterogeneous group of diseases that vary in morphology, biology,behavior and response to therapy. Triple-negative breast cancer is a subtype of tumors withaggressive clinical behavior which currently lacks effective targeted therapies. Metastasisaccounts for over 90 percent of triple-negative breast cancer -related deaths. Thus, the preventionof tumour metastasis has become an important issue. Metastasis is a multi-step process by whichprimary breast tumour cells invade neighboring tissue, translocate through the vasculature,extravasate into the surrounding tissue, and finally proliferate from microscopic growths intomacroscopic secondary tumour. Recently, microRNAs (miRNAs)acting as agents of the RNAinterference pathway, have been implicated in the regulation of a variety of cellular processes,and even the pathogenesis process of human diseases. Evidence showed that miRNAs contributeto cancer development and progression, and expression profiling analyses have revealedcharacteristic miRNA signatures in certain human cancers, such as hepatoma, breast, lung, andprostate cancer. However, the critical role played by the expressed miRNAs in specific steps ofmalignant progression, including metastasis, are still unknown. Recently, studies have beencarried out to investigate the genes and gene products that drive the metastatic process.Evidences show that miRNAs expression profiles is aberrant in breast cancer as compared withnormal breast tissues, and it can program many of the cell-biological changes needed to executethe initial steps of the invasion–metastasis cascade. The pleiotropic nature of gene regulationexhibited by miRNAs led us to hypothesize that certain miRNAs might be gave a capacity tofunction as crucial modulators of breast cancer cell metastasis. Besides, recent data support thatmiRNAs can be regulated by the change of microenvironment, such as hypoxia or stress. Theepigenetic mechanisms of miRNA regulation seem through DNA methylation and histonemodification, but the detail information is still unclear. For these reasons, we plan to connectspecific miRNAs with breast cancer metastasis, with the ambition that such associations mightprovide explanation into the causal mechanisms of cancer cell metastasis. The objective of thissub-project is to determine the relationship between miRNAs and breast cancer metastasis, aswell as the role of downstream genes of miRNAs in tumor progression. More specifically weintent in the project:(1) Identification of metastasis related miRNAs.(2) To investigate the down-stream gene target of miRNAs(3) To find out the regulatory pathway of metastasis related miRNAs(4) To clarify the relationship between hypoxia and tumour metastasis(5) Evaluation of MiRNA expression profile in clinical metastasis