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研究生：	梁玉玲 Liang, Yu-Ling
論文名稱：	SIK3與上皮性卵巢癌預後的臨床應用 Salt-inducible kinase 3 (SIK3) in prediction the prognosis of epithelial ovarian cancer
指導教授：	許耿福 Hsu, Keng-Fu
學位類別：	碩士 Master
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2017
畢業學年度：	105
語文別：	英文
論文頁數：	43
中文關鍵詞：	上皮性卵巢癌、SIK3 、CA125 、免疫組織染色
外文關鍵詞：	Epithelial ovarian cancer, SIK3, CA125, immunohistochemistry
相關次數：	點閱：99 下載：2
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卵巢癌的發生率在最近十年逐年上升，目前為婦女惡性腫瘤發生率排名第八位。在台灣地區，卵巢癌在婦女惡性腫瘤中是死亡率排名第一位的疾病。根據衛生福利部民國104年統計發表，其死亡率在近10年上升4.5 %以上。最主要的原因為超過百分之七十的卵巢癌病人在被診療時已是晚期;同時癌細胞對化學治療的抵抗性。目前臨床上在卵巢癌使用只有CA125為血清腫瘤標誌。但是CA125的專一度及敏銳度仍有不足，因此尋求新的卵巢癌生物標誌有其重要性。而在我們先前的研究中，我們使用phage library displaying 7- mer random peptides由卵巢癌病人腹水中找到新的卵巢癌 tumor – associated antigen (TAA) ; SIK3。藉由組織免疫染色法，發現SIK3基因，在卵巢癌腫瘤檢體中有六成左右有過度表現的現象，其中又以漿液狀的(serous) subtype的腫瘤佔大部分(86.4%)。細胞若高度SIK3時，會增加細胞分裂增生的能力，在小鼠中腫瘤生長的速度也增加。若抑制SIK3的表現，也發現卵巢癌細胞在小鼠的腫瘤生成的能力也受影響。在卵巢癌腫瘤檢體中有55%的敏感度，比起CA125卻有更高的特異性( 97% vs 65%)，相較於傳統CA125，SIK3 有更專一於卵巢癌的優點。因此，SIK3 有潛力成為卵巢癌檢驗或預測預後的標的指標。但先前之病例數少且無詳細病人臨床資料。因此我們進一步收集更多病人以組織免疫染色法，配合臨床病人存活資料，來解析這些問題。我們的研究方向會有以下的目標: (1) SIK3 在不同卵巢癌期別及型別的表現差異； (2)SIK3 的表現差異對於卵巢癌化學治療的阻抗性為何；(3) SIK3 是否能成為卵巢癌臨床預後診斷的生物標的。希望借由此研究計畫的結果可以了解SIK3在臨床卵巢癌的真正角色，評估它未來當作卵巢癌的生物標的可能，有助於發展新的卵巢細胞癌早期診斷腫瘤標誌及提供未來臨床治療卵巢癌治療方針的參考。利用免疫組織化學染色在上皮性卵巢癌病患之組織檢體，透過Kaplan-Meier with log-rank statistic及survival ROC 的分析，我們發現SIK3表現量較高的上皮性卵巢癌病患會有較好的存活預後( overall srvival (OS) 和progression-free survival (PFS) )。在晚期卵巢癌及漿液性卵巢癌患者身上也可以得到同樣的結論。因此，根據SIK3在組織中表現量高低，在臨床上可以提供上皮性卵巢癌病患更有效及積極的治療。藉由上述結果，接下來我們將試圖去探討SIK3與上皮性卵巢癌之間的調控關係，以及其在診斷、治療和預後的應用性，我們將進一步找尋SIK3在卵巢癌病患中血液及體液的表現量，有助於提供日後卵巢癌病患更快速方便的診斷及治療。

Epithelial ovarian carcinoma (EOC) is one of such insidious and aggressive cancers and also the most lethal gynecological malignancy in Taiwan.Despite of its relatively low incidence rate, it has the highest fatality in gynecological cancers, with about 30% of 5 year- survival rate. EOC is generally difficult to be diagnosed in early stage and was usually chemo-resistant which resulted in treatment failure. Traditionally, CA125 is the best-characterized tumor marker for advanced epithelial ovarian cancer follow-up after surgery. However, elevated serum CA125 is not only observed in advanced EOC, but also found in various physiological or other pathological conditions such as menstruation, pregnancy, endometriosis, adenomyosis, and other malignant diseases, reducing the sensitivity and specificity for ovarian cancer detection, monitoring . Thus, discovery of new cancer markers is an urgent need clinically. Previously, we have indentified a novel tumor-associated antigen salt-inducible kinase 3 (SIK3) using serological screening of a phage library displaying 7-mer random peptides with the malignant ascites antibodies of a patient with ovarian cancer. Overexpression of SIK3 markedly promoted cell proliferation, and permitted the cells to grow in mice. Decrease in SIK3 expression in high-grade SKOV3 cells consistently demonstrated its tumorigenic potency by modulating the protein levels of cell cycle regulators. Although we have observed in vitro that SIK3 is important for ovarian cancer growth, the clinicopathological conditions of patients with ovarian cancer with survival is still not clear. The first aim in this study is designed to validate the connection between with the high expression level of SIK3 and patients’ clinical prognosis. The second is to investigate the functional role of SIK3 in chemoresistant ovarian cancer. The third is to understand whether SIK3 can be as a predictor in EOC. According to immunochemical staining of the patients’ tissue from NCKUH, we found that SIK3 is highly expressed in epithelial ovarian cancer. Furthermore, comparing with epithelial ovarian cancer patients’ clinical data, the patients with higher expression of SIK3 showed better prognosis (including overall survival and progression free survival). These results are also proven in early ovarian cancer and serous type of ovarian cancer. In conclusion, we demonstrate that highly expressed SIK3 is correlated with better prognosis. Hope after finishing the project, the results can improve to discover new ovarian cancer marker, and provide possible new therapeutic target for ovarian cancer patient.

中文摘要	I
Abstract	III
Acknowledgement	V
Contents	VI
Abbreviation	VIII
Introduction	1
Epithelial ovarian cancer	1
Cancer antigen 125	2
Salt-inducible kinase 3	3
Rationale and Specific Aims	5
Material and Methods	7
1.	Immunohistochemistry analysis	7
2.	Patient collection	8
3.	Score of Immunohistochemistry staining	9
4.	Statistical analyses	10
Results	11
1.	Over expression of SIK3 staining in ovarian cancer cells	11
2.	The efficacy of SIK3 in prediction the clinical prognosis of ovarian cancer patients	11
2.1、	Patients characteristics	11
2.2、	High expression of SIK3 demonstrated better prognosis in all stages of ovarian cancer	12
2.3、	The patients with high expression of SIK3 had better overall survival in early stages of ovarian cancer	13
2.4、	The patients with high expression of SIK3 had no predominant prognosis in chemoresponse	13
Discussion	15
1.	CA125 staining and pre-op serum CA125 in prediction of the prognosis among all stages of ovarian cancer patients	15
2.	SIK3 standed for better specificity than CA125 in predicting outcome	16
3.	High expression of SIK3 standed for a vantage point on surviving of serous ovarian cancer	16
Conclusion	18
Reference	19
Figures	21
Figure 1  IHC study of different ovarian cancer tissue.	22
Figure 2  Survival analyses of all stages of disease with low, high SIK3, CA125	24
Figure 3  Survival analyses of early stage of disease with low, high SIK3, CA125	26
Figure 4  Analyses of advanced stage	27
Figure 5  Survival analyses of chemosensitive group of all stages of disease	28
Figure 6  Analyses of serous ovarian cancer	30
Figure 7  Analyses of early stage of serous ovarian cancer	31
Figure 8  Analyses of advanced stage of serous ovarian cancer	33
Figure 9  Analyses of chemosensitive group of serous ovarian cancer	34
Figure 10  Survival analysis combining SIK3 and CA125 of all stages of disease	35
Figure 11  Survival analysis combining SIK3 and CA125 of serous ovarian cancer	36
Figure 12  Time-dependent ROC curves for censored survival data and a predict marker in all stages of ovarian cancer.	38
Figure 13  Time-dependent ROC curves for censored progression free data and a predict marker in all stages of ovarian cancer.	40
Table	41
Table 1  Demographic and Clinicopathological Characteritics of the Patients	41
Table 2  Sensitivity and Specificity test of the parameters	42
Table 3  Patient characteristics (for not completing adjuvant chemotherapy)	43

                                    

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校內：2021-12-31公開
校外：2021-12-31公開

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