口腔癌為台灣十大癌症死因之一，並且是台灣男性第四常見的癌症致命殺手。儘管近年來臨床的預防、診斷與治療方法不斷地取得進展，口腔癌的發生率與死亡率在過去幾年依舊持續攀升，病患的存活率也仍未見顯著地改善，這些事實凸顯當前亟需找尋新穎的生物標記與治療標靶以協助早期診斷與治療。Shugoshin-1(Sgo1)蛋白的主要功能是在有絲分裂時期保護姊妹染色分體著絲點區域的cohesin，確保正確的染色體分離以及維持基因組的完整性。在本篇研究中，我們比較Sgo1蛋白於七株口腔鳞狀细胞癌細胞株(OSCC)以及口腔癌變前期細胞株(DOK)中之表現，並檢測口腔疾病組織微陣列切片(tissue array)中Sgo1的表現情形。總體而言，Sgo1蛋白於口腔癌組織中有表現上升之現象。為了探討Sgo1於口腔癌細胞中所扮演的角色，我們利用siRNA剔除細胞中Sgo1的表現，並發現Sgo1缺失會引起其中五株細胞的大量死亡，但另外三株卻不然。我們根據對Sgo1缺失所產生細胞反應的敏感程度，將口腔癌細胞株分為「耐受株」與「易感株」。藉由縮時顯微攝影術，我們發現Sgo1缺失的易感細胞株會滯留在有絲分裂的狀態，最終死於有絲分裂。另外，我們也觀察到在Sgo1缺失的情形下，兩類細胞株皆伴隨著有絲分裂細胞增加以及姊妹染色分體提早分離的現象。這些結果顯示Sgo1在口腔癌細胞的有絲分裂過程是極其重要的。我們更進一步證實口腔癌細胞對Sgo1缺失的敏感程度是取決於其有絲分裂檢查點(spindle assembly checkpoint)功能之穩固性，並藉由廢除有絲分裂檢查點的功能，在易感細胞株抑制因Sgo1缺失而導致有絲分裂災變(mitotic catastrophe)。最後，藉助於迴歸分析(regression analysis)，我們發現Sgo1、Bub1以及Plk-1的表現情形可望作為有絲分裂檢查點穩固性的良好指標，同時也是對Sgo1缺失的敏感程度的辨識指標。因此，我們的研究成果顯示口腔癌細胞對Sgo1之敏感性將可作為治療口腔癌的一種新的策略。

Oral cancer is one of the ten major causes of cancer death in Taiwan, ranking the fourth in men. Despite recent advances in prevention, diagnosis and treatment, the incidence and mortality of oral cancer still increased in past decades, and the overall survival rates for patients have not been improved. These highlight the urgent need for exploring novel therapeutic targets and more biomarkers for early detection and treatment. Protein Shugoshin-1 (Sgo1) functions to protect sister chromatid cohesion during mitosis and thereby ensures the fidelity of chromosome separation and the maintenance of genomic integrity. In the present study, we compared expression of Sgo1 in 7 different oral squamous cell carcinoma (OSCC) cell lines and dysplastic oral keratinocyte. The expression levels of Sgo1 were also upregulated in oral cancer tissues as revealed by tissue array, and certain OSCC cell lines. We found that the depletion of Sgo1 caused significant cell death in 5 oral cancer cell lines, but not in 3 other lines. We then categorized these cells as “resistant” and “susceptible” lines based on sensitivity to Sgo1 deficiency. Using time-lapse microscopy, we showed that susceptible cells were delayed and died in mitosis upon Sgo1 depletion. Notably, increased mitotic population and premature sister chromatid separation were detected in both resistant and susceptible lines following Sgo1 depletion. This indicates that Sgo1 is essential for mitotic progression in oral cancer cells. We demonstrated that the sensitivity to Sgo1 inhibition depends on robustness of the spindle assembly checkpoint (SAC) functionality, and the abolishment of SAC can restore mitotic catastrophe induced by Sgo1 depletion. Finally, with the help of regression analysis, we found that Sgo1, Bub1 and Plk-1 expression levels may serve as good indicator of SAC robustness and hence the sensitivity to Sgo1 depletion. Our results raise the possibility to apply Sgo1 sensitivity as a supporting therapeutic approach for treating oral cancer in the future.

Contents


Abstract 1
中文摘要 2
1. Introduction 3
1.1 Novel strategy for early detection and treatment is needed for oral cancer (OC) 3
1.2 Biological functions of shugoshin-1 (Sgo1) 4
1.3 Transcription variants of Sgo1 7
1.4 Functional role of Sgo1 in the development of different cancers 8
1.5 The general concept of spindle assembly checkpoint (SAC) and mitosis 11
1.6 Sgo1 may serve as a potential therapeutic target in OSCC 13
2. Hypothesis and specific aims 14
3. Material and methods 15
4. Results 22
4.1 Oral squamous cell carcinoma cells aberrantly express Sgo1 protein 22
4.2 Malignant and inflammatory oral tissues had high nuclear Sgo1 expression 22
4.3 The extreme extent of intercellular growth inhibition upon Sgo1 depletion enabled classification of “susceptible” and “resistant” lines 24
4.4 Depletion of Sgo1 led to mitotic cell death in susceptible lines 25
4.5 Sgo1 deficiency resulted in loss of sister chromatid cohesion in both susceptible and resistant lines 25
4.6 Sgo1 depletion caused spindle assembly checkpoint (SAC)-dependent cell death in susceptible lines 26
4.7 The responder cells had a robust SAC functionality 27
4.8 SAC robustness and endogenous Sgo1 expression level correlated with cell sensitivity to Sgo1 deficiency 27
4.9 Bub1 and Plk-1 expression level may serve as good indicator of SAC robustness and the sensitivity to Sgo1 depletion 28
4.10 Additional correlation analysis between different pairs of variables 29
5. Discussion 30
6. Figures 36
Figure 1. Expression of Sgo1 in dysplastic oral keratinocyte (DOK) and OSCC cell lines 36
Figure 2. Immunohistochemistry (IHC) revealed high nuclear expression of Sgo1 in malignant and inflammatory oral tissues 37
Figure 3. Reduction of endogenous Sgo1 protein level in cells upon Sgo1 depletion 40
Figure 4. Sgo1 depletion significantly reduced cell viability in susceptible lines 41
Figure 5. Susceptible lines underwent mitotic catastrophe upon Sgo1 depletion 42
Figure 6. Sgo1 depletion induced precocious chromosome separation in mitosis 43
Figure 7. Loss of Sgo1 increased mitotic index in both susceptible and resistant lines 44
Figure 8. Sgo1 depletion induced chromosome congression errors in OECM-1 cells 45
Figure 9. Suppression of SAC rescued susceptible lines from mitotic cell death upon Sgo1 depletion 46
Figure 10. The susceptible lines demonstrated a remarkably rising trend of mitotic index in response to nocodazole treatment with increasing concentration 47
Figure 11. IC50 of nocodazole in oral cancer cells 48
Figure 12. IC50 of BI 2536 in oral cancer cells 49
Figure 13. Correlation analysis revealed a positive correlation of Sgo1 depletion-induced growth inhibition with both SAC robustness and endogenous Sgo1 expression 50
Figure 14. Comparison of SAC component protein expression profile between susceptible and resistant lines 53
Figure 15. Model of the regulation of Sgo1 and SAC during mitosis between susceptible and resistant lines 56
Figure 16. Correlation analysis between different pairs of variables 57
7. Reference 61
8. Tables 66
9. Appendix 69

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