臺灣博碩士論文加值系統

　　HOXA10 (Homeobox A10) 是Homeobox (Hox) 家族成員之一，其功能主要在胚胎體軸發育時基因轉錄的調控。已知HOXA10會控制胚胎發育過程中子宮的形成，而在成年女性，其子宮內膜週期性的分化過程也會受到HOXA10所調控；目前已知患有子宮內膜異位症 (endometriosis) 的病人，HOXA10在其子宮基質細胞 (stromal cells) 中的表現量會有明顯的減少，但目前並不清楚HOXA10與子宮內膜異位症的發生是否有關係。在先前的研究中發現，HOXA9、HOXA10、HOXA11會在不同亞型的上皮卵巢癌 (epithelial ovarian cancer, EOC) 中表現，也會分別誘導分化成不同亞型的上皮卵巢癌，其中HOXA10會在子宮內膜型的上皮卵巢癌中表現，然而目前並沒有定量分析HOXA10在不同亞型的上皮卵巢癌間的表現情形，因此在本實驗中希望利用real-time PCR的方式來比較HOXA10在上皮卵巢癌和子宮內膜異位症組織中的表現情況，以便了解此兩種婦科疾病在賀爾蒙調控下之HOXA10不同的表現情形。於本實驗中利用real-time PCR分析HOXA10，ESR1 (ERα)，ESR2 (ERβ)和PGR (PR) 基因之表現，包括140位患有子宮內膜異位症之婦女的組織，19位沒有子宮內膜異位症之婦女組織，以及79位患有卵巢癌的婦女組織。本研究結果指出，在上皮卵巢癌中，HOXA10，ESR1和ESR2的表現相較於正常組織有1.60至2.41倍左右的增加，而PGR相較下其表現是降低的，降幅約2.80倍；然而在子宮內膜異位症病人組織中，HOXA10，ESR1和PGR的表現量相較於控制組組織是降低的情況，分別降低20.1、1.67及3.04倍，但ESR2的表現相較下增加了4.13倍。此結果顯示，在上皮卵巢癌中HOXA10的表現是較高的而在子宮內膜異位症中是較低的，與ESR1的表現情形是一致的，因而推測較高的ESR1表現會調控HOXA10表現，進而使HOXA10直接調控其下游β3-integrin的表現，因而產生此兩種不同結果的婦科疾病。另外，在文獻中指出在兩個ER中，ESR1的表現對增生的貢獻是較為主要；而在本篇研究中，我們的數據顯示在子宮內膜異位症組織中，ESR2的較高表現抑制ESR1和PGR的表現，但在卵巢癌組織中，ESR2的較高表現程度不夠高，因而不足以抑制ESR1，故造成較嚴重的增生情形。除此之外，HOXA10在卵巢癌的分化調控上扮演了一關鍵的角色，使其分化成子宮內膜亞型或漿液亞型的上皮卵巢癌。本研究為第一份評估在卵巢癌與子宮內膜異位症的發育中，荷爾蒙的調控與HOXA10的表現關係；此外也對該兩種疾病的賀爾蒙治療提供了新的觀點，並期許未來能以HOXA10對此兩婦科疾病作為一診斷的biomarker。

HOXA10 is a member of the homeobox genes family which they are transcription factors. HOXA10 is expressed in development of female reproductive tract and participates in the endometrial differentiation and may contribute to development of endometriosis and epithelial ovarian cancer (EOC). The purpose of the study is to detect and compare HOXA10 expression in the tissues of endometriosis and ovarian cancer in order to understand its role in differential regulation in these two gynaecological diseases under hormonal control. Expressions of HOXA10, ESR1 (ERα), ESR2 (ERβ) and PGR (PR) gene were quantitated in 140 patients with endometriosis and 19 women without endometriosis, and 79 ovarian cancerous tissues were determined by real-time PCR. Our data showed that expression of HOXA10, ESR1 and ESR2 were 1.60 to 2.41 folds higher and PGR was 2.80 folds lower in EOC than normal tissues. However, in endometriosis HOXA10, ESR1 and PGR were 20.1, 1.67 and 3.04 folds lower, respectively, and ESR2 was higher expression by 4.52 folds. The higher expression of HOXA10 in EOC and lower in endometriosis were coincidence with ESR1, which may support that higher expression of ESR1 manages HOXA10 to directly regulation of β3-intergin expression and then to produce the two different diseases. In addition, the expression of ESR1 is the major in the two ERs for contributes to proliferation. In this study, our data supported that overexpression of ESR2 suppress ESR1 and PGR in endometriosis, but the expression level of ESR2 was not enough for suppress ESR1 to severe proliferation. Furthermone, HOXA10 also plays a critical role for regulate the differentiation of EOC to endometrioid and mucinous subtypes. Our study was the first to establish the relationship between hormone control and the expression of HOXA10 in development of these two gynaecological diseases. These results may provide a new focus on the regulated information for hormone therapy, and provide HOXA10 as a potential biomarker for diagnosis the two diseases.

Abstract i
Abstract (Chinese) ii
Content iii

Chapter 1 Introduction 1
1.1 HOXA10 gene 1
1.1.1 Homeobox (HOX) gene 1
1.1.2 Homeobox gene and development 3
1.1.3 Homeobox gene and reproduction 4
1.1.4 HOXA10 gene 5
1.2 Sex steroid hormonal regulation of HOXA10 gene in reproductive tract 7
1.2.1 Estrogen and estrogen receptors 7
1.2.2 Progesterone and progesterone receptors 10
1.3 Ovarian cancer 11
1.3.1 Epidemiology 11
1.3.2 Surgical staging classification of ovarian cancer 12
1.3.3 Histopathology of epithelial ovarian cancer 13
1.3.4 Pathogenesis of epithelial ovarian cancer 15
1.3.5 Survival rate and ovarian cancer 17
1.3.6 HOX gene and epithelial ovarian cancer 18
1.4 Endometriosis 19
1.4.1 Epidemiology 19
1.4.2 Symptoms of endometriosis 20
1.4.3 Pathogenesis of endometriosis 20
1.4.4 Staging of endometriosis 21
1.4.5 Diagnosis of endometriosis 22
1.4.6 HOXA10 gene and endometriosis 23
1.5 Motive and specific aim 24
Chapter 2 Materials and methods 26
2.1 Experimental procedures 26
2.2 Tissue samples of ovarian cancer and endometriosis 27
2.3 Tissue RNA extraction 28
2.4 Blood RNA extraction 29
2.5 Reverse transcription 30
2.6 Real-time PCR 31
2.7 Statistical analysis 34
Chapter 3 Results 35
3.1 Patient’s clinical characteristics 35
3.1.1 Ovarian cancer 35
3.1.2 Endometriosis 36
3.2 Expression of gene profiles 38
3.2.1 Ovarian cancer 38
3.2.2 Endometriosis 39
3.3 Clinicopathological association with expression of HOXA10 in ovarian cancer 40
3.4 Clinicopathological association with expression of HOXA10 in endometriosis 43
3.5 Comparison in EOC and endometriosis 44
3.6 The profiles of gene expression in endometriotic patient during menstrual cycle 45
Chapter 4 Discussion 46
4.1 HOXA10 expression is higher in EOC but lower in endometriosis 46
4.2 Higher ESR1 expression in EOC, lower expression in endometriosis 48
4.3 The regulation of steroid hormone receptors in EOC and endometriosis 49
4.4 The expression of steroid hormone receptors in EOC and endometriosis 50
4.5 The profiles of HOXA10, ESR1 and ESR2 expression during menstrual cycle 51
Chapter 5 References 54
Chapter 6 Tables 66
Table 1. Oligonucleotide primer pairs of HOXA10, ESR1, ESR2, PGR and RPS18 for real-time PCR analysis 66
Table 2. Clinical and pathological characteristics of epithelial ovarian carcinoma patients 67
Table 3. Basic characteristic of patients with endometriosis and controls 68
Table 4. Clinical and pathological characteristics of endometriosis patients 69
Table 5. Comparison of the clinicopathologic characteristics in epithelial ovarian carcinoma patients with different expression of HOXA10 70
Table 6. Comparison of the clinicopathologic characteristics in endometriosis patients with different expression of HOXA10 71

Chapter 7 Figures 72
Figure 1. The PCR efficiency of HOXA10 primers 72
Figure 2. The PCR efficiency of ESR1 primers 73
Figure 3. The PCR efficiency of ESR2 primers 74
Figure 4. The PCR efficiency of PGR primers 75
Figure 5. The PCR efficiency of RPS18 primers 76
Figure 6. The distribution of EOC and endometriosis patients’ age 77
Figure 7. The folds of mRNA expression in patient tissues sample and ovarian cancer cell line (OV90) comparing with the normal control tissues 78
Figure 8. The profiles of the four genes expression in epithelial ovarian carcinoma patients 79
Figure 9. The profiles of the four genes expression in endometriosis patients 80
Figure 10. The expression of HOXA10 in different EOC subtypes 81
Figure 11. Comparing the mRNA expression of four genes in EOC with endometriosis 82
Figure 12. The Gene expressions in endometriotic patient’s peripheral blood during menstrual cycle 83
Chapter 8 Appendix 84

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