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標題: 修飾Mcl-1前體RNA選擇性剪接之探討Mcl-1S蛋白於基底細胞癌細胞調控細胞凋亡角色
Modification of Alternative Splicing of Mcl-1 Pre-mRNA: Role of Mcl-1S-Mediated Apoptosis in Basal Cell Carcinoma Cells
作者: 劉光庭
Liu, Kuang-Ting
關鍵字: Mcl-1S
Alternative Splicing
出版社: 醫學科技研究所
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摘要: Myeloid cell leukemia-1 (Mcl-1,又稱Mcl-1L) 是Bcl-2家族中抗凋亡類蛋白分子,能抑制細胞色素c從粒腺體釋放到細胞質,抑制caspase活化,藉此抑制細胞凋亡,增加細胞存活。Mcl-1轉錄後能透過選擇性剪接機制,轉譯成Mcl-1S蛋白,其結構上與Bcl-2家族中促凋亡類蛋白(BH-3 only proteins)相似,並具有促進細胞凋亡之功能。許多證據顯示,Mcl-1過量表現可增進人類腫瘤生長,因此其亦是腫瘤治療的標地之一。而基底細胞癌(Basal cell carcinoma, BCC)是皮膚癌中最常見的惡性腫瘤。目前已知BCC細胞可藉自體分泌IL-6增強Mcl-1(Mcl-1L)的表現,進而促進腫瘤形成及對抗細胞凋亡。因此,我們認為BCC細胞株與人類正常角質細胞(primary human keratinocyte, PHK) 中Mcl-1L與Mcl-1S表現可能有不同差異;而誘使BCC細胞株透過選擇性剪接機制,增加Mcl-1S表現並降低Mcl-1L蛋白將會促使BCC細胞株進行細胞凋亡。在本研究中我們首先比較BCC細胞株及正常角質細胞中Mcl-1L及Mcl-1S的表現並瞭解在BCC細胞株中Mcl-1L/Mcl-1S在mRNA及蛋白表現上的不平衡差異。其次,我們探討Mcl-1S蛋白在BCC細胞株內之促凋亡功能並證實過量表現Mcl-1S能調控其細胞凋亡的進行。最後,我們運用Mcl-1 Antisense Morpholino oligonucleotides 來促使BCC細胞株朝向進行Mcl-1S的選擇性剪接,並於RNA及蛋白階層證實,增加促凋亡Mcl-1S表現且同時減少抗凋亡Mcl-1L表現。如此,在BCC細胞株中改變Mcl-1S的剪接型態能誘使細胞產生凋亡。據此研究,我們利用Mcl-1 Antisense Morpholino oligos修飾改變Mcl-1前體RNA選擇性剪接後的表現型態並能誘使細胞凋亡的產生,在基底細胞癌或癌症治療上提供一新穎的策略與做法。
Myeloid cell leukemia-1(Mcl-1, also named Mcl-1L), an anti-apoptotic protein of the Bcl-2 family, acts as a critical molecule in apoptotic control, preventing cell death by inhibiting cytochrome-C release and caspase activation. Mcl-1 transcripts can be alternatively spliced into Mcl-1S (short isoform), which resembles pro-apoptotic BH-3 only proteins and induces apoptosis. Many evidences reveal that over-expression of Mcl-1 may play a role in various human tumors and may serve as a target for cancer therapy. Basal cell carcinoma (BCC) is the most common malignant tumor of skin cancer. Mcl-1(Mcl-1L) is up-regulated by autocrined IL-6, then promotes tumorgenesis and protects against apoptosis in BCC cell line. Thus, we purpose that differential expression of Mcl-1L and/or Mcl-1S may exist between transformed BCC and primary keratinocytes. In addition, hight levels of expression of Mcl-1S by shifting the splicing pattern of Mcl-1 pre-mRNA from Mcl-1L to Mcl-1S may induce the apoptosis of BCC. In this study, first, we compared the expression level of Mcl-1 variants in the established BCC cell line and primary keratinocytes and showed the unbalances of mRNA and protein expression level of Mcl-1L /Mcl-1S in BCC cell line. Second, we evaluated the pro-apoptotic function of Mcl-1S and demonstrated that over-expression of Mcl-1S could mediate apoptosis of BCC cell line. Last, we demonstrated that Mcl-1 pre-mRNA could be specifically targeted by Mcl-1 antisense morpholino oligonucleotides what shifted the splicing pattern from Mcl-1L to Mcl-1S mRNA and protein, which resulted in increasing the level of pro-apoptotic Mcl-1S and decreasing the level of anti-apoptotic Mcl-1L. The shift of Mcl-1S splicing pattern could induce apoptosis in BCC cell line. Thus, here, we provided a novel strategy for cancer therapy by antisense morpholino oligonucleotides which induce apoptosis by changing the alternative splicing pattern of Mcl-1 pre-mRNA.
其他識別: U0005-1607200817242300
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