子宮內膜癌在已開發國家中(包括台灣)是最常見的婦科癌症之一。總體來說，雖然子宮內膜癌有高的五年存活率，而且在治療後鮮少復發，但是對少數癌細胞呈現未分化型態的子宮內膜癌病人而言，癌症的惡化程度十分快速而且死亡率攀高。目前為止，尚未發現有力的分子標記以預測子宮內膜癌病人的存活。胚胎幹細胞訊息已在數種癌症中發現被活化並且導致癌症的惡性。然而，其影響力在子宮內膜癌模式中尚未被知曉。在本研究中，我們檢驗四個胚胎幹細胞轉錄因子：SOX2、OCT4、NANOG以及MYC在子宮內膜癌病人中的表現。其中，我們發現SOX2表現量與未分化細胞型態的病人以及較差的存活率有相關，而OCT4 表現量則與已分化細胞型態的病人以及較好的存活率有相關。我們發現SOX2可以促進腫瘤細胞增生並且與EGFR形成一個正回饋調控。另外，存在於腫瘤微環境的細胞激素TGF-β可以抑制SOX2的表現並進一步抑制子宮內膜癌細胞增生。總體而言，我們發現細胞激素誘導的SOX2致癌機轉，同時作為有潛力的分子標記以預測子宮內膜癌病人存活。

Endometrial carcinoma is one of the most common gynecological cancer malignancies in developed countries, including Taiwan. Although endometrial carcinoma has a favorable 5-year overall survival rate and a low relapse risk, the poorly differentiated subtype of endometrial carcinoma is aggressive with rapid metastasis. Identifying effective biomarkers for subgrouping endometrial carcinoma and predicting survival in patients is urgently needed. Embryonic stem cell signalings have been linked to tumor malignancy in several cancers; however, their involvement in endometrium oncogenesis is unclear. We thus examined the expression of SOX2, OCT4, NONOG, and MYC stemness factors in endometrial carcinoma. In four factors, SOX2 expression correlated with high-histological grade tumors and predicted a poor survival in patients with endometrial cancer, whereas OCT4 expression was associated with low-grade tumors and favored a good survival. We observed that SOX2 expression promoted proliferation and induced EGFR in a positive feedback loop in endometrial carcinoma cells. In contrast, SOX2 expression was down-regulated by TGF-β in endometrial cancer cells, while TGF-β treatment attenuated proliferation in SOX2-positive cells. Our findings support a cytokine-inducible role of SOX2 in endometrium oncogenesis with the potential to serve as a biomarker in endometrium cancer.

Abstract 1
中文摘要 2
誌謝 3
Introduction 6
Materials and Methods 10
Results 16
Discussion 21
Figures 24
References 43

References
1. Siegel, R. L., Miller, K. D. &Jemal, A. Cancer statistics, 2017. CA. Cancer J. Clin. 67, 7–30 (2017).
2. 衛生福利部國民健康署. 中華民國 103 年癌症登記報告. (2016).
3. Bokhman, J.V. Two pathogenetic types of endometrial carcinoma. Gynecol. Oncol. 15, 10–17 (1983).
4. Slomovitz, B. M. et al. Uterine papillary serous carcinoma (UPSC): A single institution review of 129 cases. Gynecol. Oncol. 91, 463–469 (2003).
5. American Cancer Society. Cancer Treatment & Survivorship Facts & Figures 2016-2017. Am. Cancer Soc. 44 (2016).
6. Zhang, Y. et al. SOX17 increases the cisplatin sensitivity of an endometrial cancer cell line. Cancer Cell Int. 1–9 (2016). doi:10.1186/s12935-016-0304-7
7. Clarke, M. F. et al. Cancer stem cells - Perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res. 66, 9339–9344 (2006).
8. Clarke, M. F. & Fuller, M. Essay Stem Cells and Cancer : Two Faces of Eve. 1111–1115 (2006). doi:10.1016/j.cell.2006.03.011
9. Takahashi, K. et al. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. Cell 131, 861–872 (2007).
10. Yu, J., Vodyanik, M. &Smuga-Otto, K. Induced pluripotent stem cell lines derived from human somatic cells. Science (80-. ). 318, 1917–1920 (2007).
11. Ben-porath, I. et al. An embryonic stem cell – like gene expression signature in poorly differentiated aggressive human tumors. 40, 499–507 (2008).
12. Guo, G. et al. Resolution of Cell Fate Decisions Revealed by Single-Cell Gene Expression Analysis from Zygote to Blastocyst. Dev. Cell 18, 675–685 (2010).
13. Boyer, L. A. et al. Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells. 122, 947–956 (2005).
14. Chen, J. et al. Pituitary Progenitor Cells Tracked Down by Side Population Dissection. Stem Cells 27, 1182–1195 (2009).
15. Chen, Y. et al. The Molecular Mechanism Governing the Oncogenic Potential of SOX2 in Breast Cancer *. 283, 17969–17978 (2008).
16. Hussenet, T. et al. SOX2 Is an Oncogene Activated by Recurrent 3q26 . 3 Amplifications in Human Lung Squamous Cell Carcinomas. 5, (2010).
17. Bass, A. J. et al. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat. Genet. 41, 1238–1242 (2009).
18. Chou, Y. T. et al. The emerging role of SOX2 in cell proliferation and survival and its crosstalk with oncogenic signaling in lung cancer. Stem Cells 31, 2607–2619 (2013).
19. Mori, Y. et al. Sox2-dependent inhibition of p21 is associated with poor prognosis of endometrial cancer. (2017). doi:10.1111/cas.13196
20. Thomson, M. et al. Pluripotency Factors in Embryonic Stem Cells Regulate Differentiation into Germ Layers. Cell 145, 875–889 (2011).
21. Franko, A. J. Oxygen Diffusion In The Multicell Spheroid In Vitro Tumor Model : Effects On Cell Survival And Radiation Response. (1977).
22. Kong, F. et al. Biochemical and Biophysical Research Communications Preliminary identi fi cation of endometrial cancer stem cells in vitro and in vivo. 4–11 (2017). doi:10.1016/j.bbrc.2017.06.070
23. Lee, J. et al. The Human OCT-4 Isoforms Differ in Their Ability to Confer Self-renewal *. 281, 33554–33565 (2006).
24. Wang, X. et al. Alternative Translation of OCT4 by an Internal Ribosome Entry Site and its Novel Function in Stress Response. Stem Cells 27, 1265–1275 (2009).
25. Gao, Y. et al. The Novel Function of OCT4B Isoform-265 in Genotoxic Stress YUAN. stem cell 30, 665–672 (2012).
26. Miettinen, I. V. I. J. et al. Uterine and Vaginal Organ Growth Requires Epidermal Growth Factor Receptor Signaling from Stroma *. 139, (1998).
27. Large, M. J. et al. The Epidermal Growth Factor Receptor Critically Regulates Endometrial Function during Early Pregnancy. 10, (2014).
28. Miturski, R., Semczuk, A.,& Postawski, J. J. Epidermal growth factor receptor immunostaining and epidermal growth factor receptor-tyrosine kinase activity in proliferative and neoplastic human endometrium. Tumour Biol 21, 358–366 (2000).
29. Hu, Q. et al. The Egf Receptor-Sox2-Egf Receptor Feedback Loop Positively Regulates the Self-Renewal of Neural Precursor Cells. Stem cell 28, 279–286 (2010).
30. Gao, Y., Li, S. &Li, Q. Uterine epithelial cell proliferation and endometrial hyperplasia : evidence from a mouse model. 20, 776–786 (2014).
31. Boiani, M. et al. Oct4 distribution and level in mouse clones : consequences for pluripotency. 1209–1219 (2002). doi:10.1101/gad.966002.transplanted
32. Guang, J.P., Chang, Z.Y, & Pei, D. Stem cell pluripotency and transcription factor Oct4. 12, 321–329 (2002).
33. Press, A. I. N. OCT4 expression in human non-small cell lung cancer : implications. 8, 393–397 (2009).
34. Gao, Y. et al. The novel OCT4 spliced variant OCT4B1 can generate three protein isoforms by alternative splicing into OCT4B. 37, 461-465 (2010)
35. Brehm, A. et al. The Carboxy-Terminal Transactivation Domain of Oct-4 Acquires Cell Specificity through the POU Domain. 17, 154–162 (1997).
36. Guo, C. et al. A novel variant of Oct3 / 4 gene in mouse embryonic stem cells. Stem Cell Res. 9, 69–76 (2012).