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作者(中文):王律涵
作者(外文):Wang, Lyu Han
論文名稱(中文):鑑別蛋白質Shugoshin-1作為有潛力的肝癌治療之標靶
論文名稱(外文):Identify protein Shugoshin-1 as a potential therapeutic target for hepatocellular carcinoma
指導教授(中文):王慧菁
指導教授(外文):Wang, Lily Hui-Ching
口試委員(中文):楊立威
李佳霖
劉俊揚
趙瑞益
學位類別:博士
校院名稱:國立清華大學
系所名稱:分子與細胞生物研究所
學號:9780811
出版年(民國):104
畢業學年度:103
語文別:英文中文
論文頁數:74
中文關鍵詞:有絲分裂肝癌乙型肝癌病毒標靶治療
外文關鍵詞:MitosisShugoshin-1Hepatocellular carcinomaTargeted therapyHepatitis b virus
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Shugoshin-1(Sgo1)的功能在於保護著絲點上的cohesin以確保正確的染色體分離和維持基因組的完整性。有絲分裂期間,Plk-1磷酸化cohesin的亞單位SA2並導致cohesin離開染色體臂。相對的,著絲點的cohesin仍然停留於著絲點。原因是Sgo1與PP2A可以抵消Plk1對著絲點的cohesin的磷酸化。因此,著絲點的cohesin持續捆住姊妹染色體直到細胞進入anaphase。在本篇研究中,我們發現Plk1的活性不會影響Sgo1在有絲分裂期間的蛋白質表現和細胞內的定位。另一方面,我們在正常組織和轉型細胞株內偵測Sgo1異構體 (isoform) 的信使核糖核酸的表現。結果顯示轉型細胞株皆有表現Sgo1異構體的信使核糖核酸。除了胸線和睪丸,我們在其他正常組織中則無法偵測到Sgo1異構體的表現。而與永生細胞株RPE-1和NeHepLxHT比較,Sgo1蛋白會大量表現在轉型細胞株,如: HeLa、HuH-7、WRL-68、HepG2以及HepaRG。與周邊非肝癌樣本比較,我們也發現肝癌會大量表現Sgo1的信使核糖核酸和蛋白質。利用小分子干擾核糖核酸抑制Sgo1的表現導致了HeLa和HuH-7細胞的染色體缺失並使紡錘體裝配檢驗點 (spindle assembly checkpoint) 持續活性化。這個結果阻止細胞分裂的進行並引起細胞大量死亡於有絲分裂期。但永生細胞株RPE-1和NeHepLxHT並不受到抑制Sgo1的表現而大量死亡於有絲分裂期。另外,我們也發現在肝癌的周邊正常組織中,乙型肝炎病毒的表現與Sgo1蛋白的表現呈正相關。NeHepLxHT細胞株表現LHBs的細胞也有Sgo1大量表現的情況,並在有絲分裂的過程中伴隨染色體缺失。這些結果顯示Sgo1對於轉型細胞株和帶有LHBs蛋白的肝細胞在有絲分裂的過程中是重要的調控蛋白。這些結果顯示Sgo1可能是一個治療肝癌的新標靶,尤其是受到乙型肝炎病毒感染的肝癌。

Protein Shugoshin-1 (Sgo1) functions to protect centromeric cohesion and is essential for proper chromosome segregation and genomic integrity. During mitosis, Plk-1 phosphorylates SA2 subunit of cohesin, and thereby cohesin dissociates from chromosome arm. In contrast, centromeric cohesin is still kept at centromere due to the reason that Sgo1-protein phosphatase 2A (PP2A) counteracts Plk1-mediated phosphorylation at centromeric cohesin. Therefore, centromeric cohesin still tethers sister chromatids together until the onset of anaphase. In this study, we find that protein stability and localization of Sgo1 are independent of Plk1 activity during mitosis. In addition, we examined expression levels of Sgo1 isoforms in normal tissue cDNA and transformed cell lines by conventional reverse transcription-PCR. All Sgo1 isoforms are detected in the transformed cell lines, but not in most normal tissues, expect for thymus and testis. In contrast to hTERT-immortalized cell lines, we find that Sgo1 protein is highly expressed in transformed cell lines, such as HeLa, HuH-7, WRL-68, HepG2, and HepaRG. We also demonstrate that mRNA and the protein levels of Sgo1 significantly increased in HCC, compared with in adjacent non-HCC regions. The depletion of Sgo1 induces chromosome instability and mitotic cell death in HeLa and HuH-7 cells, as a result of spindle assembly checkpoints activation. This effect is not detected in hTERT-immortalized cell lines such as RPE-1 and NeHepLxHT. Notably, hepatitis B virus (HBV) is positively correlated with Sgo1 expression at non-HCC regions. Overexpression of viral large surface proteins (LHBS) increases Sgo1 expression on NeHepLxHT cells along with increased chromosome instabilities. These results demonstrated that Sgo1 is an important modulator for mitotic progression in transformed cells and hepatocytes carrying HBV-LHBS protein. We suggest that Sgo1 is a promising and novel therapeutic target for HCC, especially those related to HBV infection.
Contents

Abstract 1
中文摘要 2
1. Introduction 3
1.1 The overview of spindle assembly checkpoint and mitosis 3
1.2 Shugoshin-1 (Sgo1) cooperates with protein phosphatase 2A to preserve centromeric cohesin during mitosis 3
1.3 Sgo1 localization is involved in tension sensing 5
1.4 The isoforms of Sgo1 play different functions in mitosis 6
1.5 The expression of Sgo1 in cancer tissues 6
1.6 Hepatocellular carcinoma (HCC) and Hepatitis B Virus (HBV) 7
1.7 Novel therapeutic target is needed for HCC 8
2. Hypothesis and Specific Aims 9
3. Materials and methods 10
4. Results 15
4.1 Plk1 is not involved in protein stability and localization of Sgo1 15
4.2 Transformed cell lines express high level of Sgo1 mRNA 15
4.3 Human transformed cell lines express abundant Sgo1 protein 16
4.4 Sgo1 is upregulated in hepatocellular carcinoma (HCC) 17
4.5 Depletion of Sgo1 induces various mitotic defects in hepatoma cells 18
4.6 SAC is involved in mitotic arrest upon Sgo1 depletion 19
4.7 Overexpression of Sgo1 induces chromosome instability 20
4.8 HBV infection is positively correlated with Sgo1 expression in the liver 20
4.9 Sgo1 is essential for viability of hepatocytes carrying LHBS protein 21
4.10 Upstream regulators of Sgo1 is not yet found 22
5. Discussion 24
6. References 29
7. Figures 40
Figure 1. The protein expression of Sgo1 upon BI2536 treatment in HeLa cells 40
Figure 2. Subcellular localization of Sgo1 upon BI2536 treatment in HeLa cells 41
Figure 3. Schematic diagram of Sgo1 isoforms 42
Figure 4. The messenger RNA expression of Sgo1 in normal tissues 43
Figure 5. The messenger RNA expression of Sgo1 isoforms in various human cancer cells 44
Figure 6. Clarification of Sgo1 protein expression in HeLa cells 45
Figure 7. Sgo1 protein expression in human various cell lines 46
Figure 8. Expression of Sgo1 mRNA in HCC and adjacent liver tissues 47
Figure 9. The expression levels of Sgo1 mRNA in 60 paired specimens of HCC and non -HCC. 48
Figure 10. The protein levels of Sgo1, HSP70, and PCNA in 21 paired cases specimens of HCC (H) and adjacent non-HCC (N) 49
Figure 11. Representative immunohistochemistry images indicated subcellular localization of Sgo1 in HCC and adjacent non-HCC regions 50
Figure 12. The depletion of Sgo1 reduced cell viability in transformed cells 51
Figure 13. Morphology of indicated cell lines upon Sgo1 depletion 52
Figure 14. Depletion of Sgo1 initiated mitotic cell death in transformed cell lines 53
Figure 15. Depletion of Sgo1 increased cells death in mitosis in transformed cells 54
Figure 16. Sgo1 depletion increased micronucleation in HuH-7 cells 55
Figure 17. Sgo1 depletion caused chromosome premature separation in HuH-7, RPE-1, and NeHepLxHT cells 56
Figure 18. Inhibition of SAC decreased mitotic cell death upon Sgo1 depletion 57
Figure 19. Inhibition of Mad2 decreased mitotic cell death upon Sgo1 depletion 58
Figure 20. The regulation of Sgo1 and SAC during mitosis 59
Figure 21. Overexpression of Sgo1 in HeLa cells 60
Figure 22. Sgo1 overexpression slightly increased chromosome congression 61
Figure 23. Sgo1 overexpression slightly increased chromosome bridges and lagging chromosome 62
Figure 24. Sgo1 overexpression slightly increased chromosome bridges and lagging chromosome. 63
Figure 25. Representative immunohistochemistry images demonstrated the expression and localization of Sgo1 and LHBs in hepatocytes. 64
Figure. 26. Protein levels of Sgo1 protein were highly expressed in HBV-infected non-HCC. 65
Figure 27. Sgo1 protein were overexpressed in LHBs-positive NeHepLxHT cells. 66
Figure 28. NeHepLxHT cells carrying LHBS increased mitotic index upon nocodazole treatment. 67
Figure 29. Precocious chromosome separation were caused upon Sgo1 depletion in LHBs-positive NeHepLxHT cells. 68
Figure 30. Treatment of SAC inhibitors decreased mitotic index and mitotic cell death upon Sgo1 depletion in LHBS-positive NeHepLxHT cells. 69
Figure 31. LHBS-positive NeHepLxHT cells did not change subcellular localization of Sgo1 but increased chromosome bridges during mitosis. 70
Figure 32. The levels of Sgo1 protein upon treatment of different chemicals in LHBS-positive NeHepLxHT cells. 71
Figure 33. Statistic results of Sgo1 protein intensity upon different chemical treatment in NeHepLxHT LHBS-positive cells. 72
8. Tables 73
9. Appendix 77
6. References
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Bakhoum, S.F., Genovese, G., and Compton, D.A. (2009). Deviant kinetochore microtubule dynamics underlie chromosomal instability. Curr Biol 19, 1937-1942.
Boss, D.S., Schwartz, G.K., Middleton, M.R., Amakye, D.D., Swaisland, H., Midgley, R.S., Ranson, M., Danson, S., Calvert, H., Plummer, R., et al. (2010). Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours. Ann Oncol 21, 884-894.
Cheeseman, I.M., Chappie, J.S., Wilson-Kubalek, E.M., and Desai, A. (2006). The conserved KMN network constitutes the core microtubule-binding site of the kinetochore. Cell 127, 983-997.
Chen, D.S. (2010). Toward elimination and eradication of hepatitis B. J Gastroenterol Hepatol 25, 19-25.
Chen, K.F., Chen, H.L., Tai, W.T., Feng, W.C., Hsu, C.H., Chen, P.J., and Cheng, A.L. (2011). Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells. J Pharmacol Exp Ther 337, 155-161.
De Antoni, A., Pearson, C.G., Cimini, D., Canman, J.C., Sala, V., Nezi, L., Mapelli, M., Sironi, L., Faretta, M., Salmon, E.D., et al. (2005). The Mad1/Mad2 complex as a template for Mad2 activation in the spindle assembly checkpoint. Curr Biol 15, 214-225.
Dickson, M.A., and Schwartz, G.K. (2009). Development of cell-cycle inhibitors for cancer therapy. Current oncology 16, 36-43.
Fang, G., Yu, H., and Kirschner, M.W. (1998). The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation. Genes Dev 12, 1871-1883.
Finn, R.S., Crown, J.P., Lang, I., Boer, K., Bondarenko, I.M., Kulyk, S.O., Ettl, J., Patel, R., Pinter, T., Schmidt, M., et al. (2015). The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 16, 25-35.
Foley, E.A., Maldonado, M., and Kapoor, T.M. (2011). Formation of stable attachments between kinetochores and microtubules depends on the B56-PP2A phosphatase. Nat Cell Biol 13, 1265-1271.
Fry, D.W., Harvey, P.J., Keller, P.R., Elliott, W.L., Meade, M., Trachet, E., Albassam, M., Zheng, X., Leopold, W.R., Pryer, N.K., et al. (2004). Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 3, 1427-1438.
Hahntow, I.N., Schneller, F., Oelsner, M., Weick, K., Ringshausen, I., Fend, F., Peschel, C., and Decker, T. (2004). Cyclin-dependent kinase inhibitor Roscovitine induces apoptosis in chronic lymphocytic leukemia cells. Leukemia 18, 747-755.
Hara, K., Zheng, G., Qu, Q., Liu, H., Ouyang, Z., Chen, Z., Tomchick, D.R., and Yu, H. (2014). Structure of cohesin subcomplex pinpoints direct shugoshin-Wapl antagonism in centromeric cohesion. Nat Struct Mol Biol 21, 864-870.
Hauf, S., Roitinger, E., Koch, B., Dittrich, C.M., Mechtler, K., and Peters, J.M. (2005). Dissociation of cohesin from chromosome arms and loss of arm cohesion during early mitosis depends on phosphorylation of SA2. PLoS Biol 3, e69.
Hauf, S., Waizenegger, I.C., and Peters, J.M. (2001). Cohesin cleavage by separase required for anaphase and cytokinesis in human cells. Science 293, 1320-1323.
Horvat, R.T. (2011). Diagnostic and Clinical Relevance of HBV Mutations. Labmedicine 42, 488-496.
Huang, M., and Liu, G. (1999). The study of innate drug resistance of human hepatocellular carcinoma Bel7402 cell line. Cancer Lett 135, 97-105.
Huang, S.N., and Chisari, F.V. (1995). Strong, sustained hepatocellular proliferation precedes hepatocarcinogenesis in hepatitis B surface antigen transgenic mice. Hepatology 21, 620-626.
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Matsuura, S., Kahyo, T., Shinmura, K., Iwaizumi, M., Yamada, H., Funai, K., Kobayashi, J., Tanahashi, M., Niwa, H., Ogawa, H., et al. (2013). SGOL1 variant B induces abnormal mitosis and resistance to taxane in non-small cell lung cancers. Sci Rep 3, 3012.
McGuinness, B.E., Hirota, T., Kudo, N.R., Peters, J.M., and Nasmyth, K. (2005). Shugoshin prevents dissociation of cohesin from centromeres during mitosis in vertebrate cells. PLoS Biol 3, e86.
Meppelink, A., Kabeche, L., Vromans, M.J., Compton, D.A., and Lens, S.M. (2015). Shugoshin-1 balances Aurora B kinase activity via PP2A to promote chromosome bi-orientation. Cell Rep 11, 508-515.
Morrow, C.J., Tighe, A., Johnson, V.L., Scott, M.I., Ditchfield, C., and Taylor, S.S. (2005). Bub1 and aurora B cooperate to maintain BubR1-mediated inhibition of APC/CCdc20. J Cell Sci 118, 3639-3652.
Nakabayashi, H., Taketa, K., Miyano, K., Yamane, T., and Sato, J. (1982). Growth of human hepatoma cells lines with differentiated functions in chemically defined medium. Cancer research 42, 3858-3863.
Raghavan, P., Tumati, V., Yu, L., Chan, N., Tomimatsu, N., Burma, S., Bristow, R.G., and Saha, D. (2012). AZD5438, an inhibitor of Cdk1, 2, and 9, enhances the radiosensitivity of non-small cell lung carcinoma cells. Int J Radiat Oncol Biol Phys 84, e507-514.
Reid, Y., Gaddipati, J.P., Yadav, D., and Kantor, J. (2009). Establishment of a human neonatal hepatocyte cell line. In Vitro Cell Dev Biol Anim 45, 535-542.
Salic, A., Waters, J.C., and Mitchison, T.J. (2004). Vertebrate shugoshin links sister centromere cohesion and kinetochore microtubule stability in mitosis. Cell 118, 567-578.
Scanlan, M.J., and Jager, D. (2001). Challenges to the development of antigen-specific breast cancer vaccines. Breast cancer research : BCR 3, 95-98.
Sudakin, V., Chan, G.K., and Yen, T.J. (2001). Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2. J Cell Biol 154, 925-936.
Sumara, I., Gimenez-Abian, J.F., Gerlich, D., Hirota, T., Kraft, C., de la Torre, C., Ellenberg, J., and Peters, J.M. (2004). Roles of polo-like kinase 1 in the assembly of functional mitotic spindles. Curr Biol 14, 1712-1722.
Sumara, I., Vorlaufer, E., Stukenberg, P.T., Kelm, O., Redemann, N., Nigg, E.A., and Peters, J.M. (2002). The dissociation of cohesin from chromosomes in prophase is regulated by Polo-like kinase. Mol Cell 9, 515-525.
Tai, W.T., Cheng, A.L., Shiau, C.W., Liu, C.Y., Ko, C.H., Lin, M.W., Chen, P.J., and Chen, K.F. (2012). Dovitinib induces apoptosis and overcomes sorafenib resistance in hepatocellular carcinoma through SHP-1-mediated inhibition of STAT3. Mol Cancer Ther 11, 452-463.
Tanaka, T., Fuchs, J., Loidl, J., and Nasmyth, K. (2000). Cohesin ensures bipolar attachment of microtubules to sister centromeres and resists their precocious separation. Nat Cell Biol 2, 492-499.
Tang, Z., Bharadwaj, R., Li, B., and Yu, H. (2001). Mad2-Independent inhibition of APCCdc20 by the mitotic checkpoint protein BubR1. Dev Cell 1, 227-237.
Tang, Z., Shu, H., Qi, W., Mahmood, N.A., Mumby, M.C., and Yu, H. (2006). PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation. Dev Cell 10, 575-585.
Thornton, B.R., and Toczyski, D.P. (2003). Securin and B-cyclin/CDK are the only essential targets of the APC. Nat Cell Biol 5, 1090-1094.
Torre, L.A., Bray, F., Siegel, R.L., Ferlay, J., Lortet-Tieulent, J., and Jemal, A. (2015). Global Cancer Statistics, 2012. Ca-Cancer J Clin 65, 87-108.
van Malenstein, H., Dekervel, J., Verslype, C., Van Cutsem, E., Windmolders, P., Nevens, F., and van Pelt, J. (2013). Long-term exposure to sorafenib of liver cancer cells induces resistance with epithelial-to-mesenchymal transition, increased invasion and risk of rebound growth. Cancer Lett 329, 74-83.
Waizenegger, I.C., Hauf, S., Meinke, A., and Peters, J.M. (2000). Two distinct pathways remove mammalian cohesin from chromosome arms in prophase and from centromeres in anaphase. Cell 103, 399-410.
Walsby, E., Lazenby, M., Pepper, C., and Burnett, A.K. (2011). The cyclin-dependent kinase inhibitor SNS-032 has single agent activity in AML cells and is highly synergistic with cytarabine. Leukemia 25, 411-419.
Wang, H.C., Chang, W.T., Chang, W.W., Wu, H.C., Huang, W., Lei, H.Y., Lai, M.D., Fausto, N., and Su, I.J. (2005). Hepatitis B virus pre-S2 mutant upregulates cyclin A expression and induces nodular proliferation of hepatocytes. Hepatology 41, 761-770.
Wang, X., Yang, Y., and Dai, W. (2006). Differential subcellular localizations of two human Sgo1 isoforms: implications in regulation of sister chromatid cohesion and microtubule dynamics. Cell Cycle 5, 635-640.
Wang, X., Yang, Y., Duan, Q., Jiang, N., Huang, Y., Darzynkiewicz, Z., and Dai, W. (2008). sSgo1, a major splice variant of Sgo1, functions in centriole cohesion where it is regulated by Plk1. Dev Cell 14, 331-341.
Woodhouse, J.R., and Ferry, D.R. (1995). The genetic basis of resistance to cancer chemotherapy. Annals of medicine 27, 157-167.
Wu, H.C., Tsai, H.W., Teng, C.F., Hsieh, W.C., Lin, Y.J., Wang, L.H., Yuan, Q., and Su, I.J. (2014). Ground-glass hepatocytes co-expressing hepatitis B virus X protein and surface antigens exhibit enhanced oncogenic effects and tumorigenesis. Hum Pathol 45, 1294-1301.
Xie, G., Tang, H., Wu, S., Chen, J., Liu, J., and Liao, C. (2014). The cyclin-dependent kinase inhibitor SNS-032 induces apoptosis in breast cancer cells via depletion of Mcl-1 and X-linked inhibitor of apoptosis protein and displays antitumor activity in vivo. Int J Oncol 45, 804-812.
Xu, Z., Cetin, B., Anger, M., Cho, U.S., Helmhart, W., Nasmyth, K., and Xu, W. (2009). Structure and function of the PP2A-shugoshin interaction. Mol Cell 35, 426-441.
Yamada, H.Y., Yao, Y., Wang, X., Zhang, Y., Huang, Y., Dai, W., and Rao, C.V. (2012). Haploinsufficiency of SGO1 results in deregulated centrosome dynamics, enhanced chromosomal instability and colon tumorigenesis. Cell Cycle 11, 479-488.
Yang, J., Ikezoe, T., Nishioka, C., and Yokoyama, A. (2012). A novel treatment strategy targeting shugoshin 1 in hematological malignancies. Leuk Res.
Yuen, K.W.Y. (2001). Chromosome Instability (CIN), Aneuploidy and Cancer. In eLS (John Wiley & Sons, Ltd).
Zhu, A.X. (2006). Systemic therapy of advanced hepatocellular carcinoma: how hopeful should we be? Oncologist 11, 790-800.

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