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標題: SLAN分子功能的探討及與肺癌之關係
The Function of SLAN and its Relationship with Lung Cancer
作者: 夏君毅
Hsia, Jiun-Yi
關鍵字: SLAN;肺癌;SLAN
出版社: 分子生物學研究所
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Perimembrane Aurora-A expression is a significant prognostic factor in correlation with proliferative activity in non-small-cell lung cancer (NSCLC). Ann Surg Oncol 2008;15:547-554. 8 Agnese V, Bazan V, Fiorentino FP, et al. The role of Aurora-A inhibitors in cancer therapy. Ann Oncol 2007;6:vi47-52. 9 Boss DS, Beijnen JH, Schellens JH. Clinical experience with aurora kinase inhibitors: a review. Oncologist 2009;14:780-793. 10 Carvajal RD, Tse A, Schwartz GK. Aurora kinases: new targets for cancer therapy. Clin Cancer Res 2006;12:6869-6875. 11 Cheung CH, Coumar MS, Hsieh HP, et al. Aurora kinase inhibitors in preclinical and clinical testing. Expert Opin Investig Drugs 2009;18:379-398. 12 Coumar MS, Cheung CH, Chang JY, et al. Advances in Aurora kinase inhibitor patents. Expert Opin Ther Pat 2009; 19:321-356. 13 Gautschi O, Heighway J, Mack PC, et al. Aurora kinases as anticancer drug targets. Clin Cancer Res 2008;14:1639-1648. 14 Kitzen JJ, de Jonge MJ, Verweij J. Aurora kinase inhibitors. Crit Rev Oncol Hematol 2010;73:99-110. 15 Moore AS, Blagg J, Linardopoulos S, et al. Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias. Leukemia 2010;24:671-678. 16. Copeland PR, Driscoll DM. RNA binding proteins and selenocysteine. Biofactors 2001;14:11-16. 17 Mudge J, Miller NA, Khrebtukova I, et al. Genomic Convergence Analysis of Schizophrenia: mRNA Sequencing Reveals Altered Synaptic Vesicular Transport in Post-Mortem Cerebellum. PLoS ONE 2008;3:e3625. 18 Hawse JR, Hejtmancik JF, Huang Q, et al. Identification and functional clustering of global gene expression differences between human age-related cataract and clear lenses. Mol Vis 2003;9:515-537. 19 Cahill S, Smyth P, Finn SP, et al. Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model. Mol Cancer 2006;5:70. 20 Yu JX, Sieuwerts AM, Zhang Y,et al. Pathway analysis of gene signatures predicting metastasis of node-negative primary breast cancer. BMC Cancer 2007; 7:182. 21 Bischoff JR, Anderson L, Zhu Y, et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 1998; 17:3052-3065. 22 Zhou H, Kuang J, Zhong L Kuo WL, et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 1998;20:189-193. 23 Wang X, Zhou YX, Qiao W Tominaga Y, et al. Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation. Oncogene 2006;25:7148-7158. 24 Crane R, Gadea B, Littlepage L, et al. Aurora A, meiosis and mitosis. Biol Cell 2004;96:215-229. 25 Marumoto T, Zhang D, Saya H. Aurora-A - a guardian of poles. Nat Rev Cancer 2005;59:42-450. 26 Barr AR, Gergely F. Aurora-A: the maker and breaker of spindle poles. J Cell Sci 2007;120:2987-2996. 27 Su LJ, Chang CW, Wu YC, et al. Selection of DDX5 as a novel internal control for Q-RT-PCR from microarray data using a block bootstrap re-sampling scheme. BMC Genomics 2007;8:140. 28 Lin YS, Su LJ, Yu CT, et al. Gene expression profiles of the aurora family kinases. Gene Expr 2006;13:15-26. 29 Tsai MY, Wang S, Heidinger JM, et al. A mitotic lamin B matrix induced by RanGTP required for spindle assembly. Science 2006;311:1887-1893. 30 Walker DL, Wang D, Jin Y, et al. Skeletor, a novel chromosomal protein that redistributes during mitosis provides evidence for the formation of a spindle matrix. J Cell Biol 2000;151:1401-1412. 31 Caban K, Copeland PR. Size matters: a view of selenocysteine incorporation from the ribosome. Cell Mol Life Sci 2006;63:73-81. 32 Yu CT, Hsu JM, Lee YC, et al. Phosphorylation and stabilization of HURP by Aurora-A: implication of HURP as a transforming target of Aurora-A. Mol Cell Biol 2005;25:5789-5800. 33 Arbitrario JP, Belmont BJ, Evanchik MJ, et al. SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo. Cancer Chemother Pharmacol 2009;65:707-717. 34 Benten D, Keller G, Quaas A, et al. Aurora kinase inhibitor PHA-739358 suppresses growth of hepatocellular carcinoma in vitro and in a xenograft mouse model. Neoplasia 2009;11:934-944. 35 Lin ZZ, Hsu HC, Hsu CH, et al. The Aurora kinase inhibitor VE-465 has anticancer effects in pre-clinical studies of human hepatocellular carcinoma. J Hepatol 2009;50:518-527. 36 Ochi T, Fujiwara H, Yasukawa M. Aurora-A kinase: a novel target both for cellular immunotherapy and molecular target therapy against human leukemia. Expert Opin Ther Targets 2009;13:1399-1410. 37 VanderPorten EC, Taverna P, Hogan JN, et al. The Aurora kinase inhibitor SNS-314 shows broad therapeutic potential with chemotherapeutics and synergy with microtubule-targeted agents in a colon carcinoma model. Mol Cancer Ther 2009;8:930-939.
In an attempt to search for genes with abnormal expression in cancers, SLAN (Suppressed in lung cancer, also known as KIAA0256) is found underexpressed in human lung cancer tissues by quantitative real-time PCR (Q-RT-PCR). SLAN and its deletion mutants are localized to many subcellular locations such as endoplasmic reticulum (ER), nucleus, nucleolus, spindle pole and midbody, suggesting SLAN may function as a multifunctional protein. Overexpression of SLAN per se or its short hairpin RNAs (shRNAs) inhibits or accelerates cell proliferation through prolonging or shortening mitosis. Time-lapse microscopic recording reveals that cells overexpressing exogenous SLAN are arrested in mitosis or cannot undergo cytokinesis. SLAN 2-551 mutants drastically arrest cells in mitosis, where α- and γ-tubulin are disorganized. SLAN employs C-terminal to interact with Aurora-A, a key mitosis regulator and an oncogenic kinase associated with a wide range of human cancers. SLAN negatively regulates the activity of Aurora-A by directly inhibiting kinase activity in vitro or reducing the level of active Aurora-A in cells. SLAN is frequently reduced in lung cancer tissues overexpressing Aurora-A, arguing for the necessity to suppress SLAN during the Aurora-A-associated cancer formation. Taken together, we have identified a novel protein SLAN downregulated in lung caner and able to inhibit cell proliferation and Aurora-A.

為了嚐試尋找在癌症組織中不正常表現的基因,我們以肺癌作為研究的目標,經由Q-RT-PCR之方法,發現在人類肺癌組織中,SLAN (Suppressed in Lung cANcer,又稱為KIAA0256)這個尚未被充分研究的新的基因有表現偏低的現象。這個研究的目的,即在於探討SLAN分子在細胞內的功能及與肺癌的關係。
本研究利用SLAN 之 full length或是各種的deletion mutants,或是SLAN 的shRNA,表現在293T或各種肺癌的cell lines中,進而研究它們對於細胞增生,細胞週期,細胞分裂的進行,及紡綞絲排列之影響。
在本研究中,我們發現SLAN及它的各種deletion mutants分布在細胞內的許多位置,包括內質網,細胞核,核仁,極紡綞體等,顯示SLAN可能是一個具有多種功能的蛋白質。將SLAN基因過度表現,會經由延長有絲分裂而抑制細胞增生。反之,以SLAN之shRNA作用後,會經由縮短有絲分裂而加速細胞增生。連續定時之顯微鏡觀察顯示,細胞過度表現外來的SLAN時,會使細胞停止在有絲分裂或不能進行細胞質分裂。SLAN 2-551這個deletion mutant讓細胞停止在有絲分裂期的比例最高,同時呈現α及γ-tubulin混亂的排列。Aurora-A,是一個關鍵的有絲分裂調控者,並與多種人類癌症相關的致癌激酶。SLAN以C端與Aurora-A交互作用。同時SLAN會直接抑制激酶活動而反向調控Aurora-A的活性,或在細胞內降低具有活性的Aurora-A。在過度表現Aurora-A的肺癌組織中,SLAN時常會降低表現,也使得在與Aurora-A相關的癌症形成中,抑制SLAN基因的機轉值得進一步探討。
其他識別: U0005-2308201117255900
Appears in Collections:分子生物學研究所

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