臺灣博碩士論文加值系統

甲狀腺癌在台灣女性的癌症中排行第八位，雖然如此，甲狀腺癌症形成的機轉至今仍然不是很清楚。甲狀腺細針穿刺合併細胞學檢查廣被運用來作為是手術前診斷甲狀腺癌最重要的方法，這個方法的敏感性高達80%以上，但前提是必需取得適當的檢體、還有醫師的經驗必須要足夠。除此以外，有高達30%的甲狀腺瘤屬於甲狀腺濾泡腫瘤，它的特色是目前無法在術前診斷是良性或是惡性腫瘤。因此如果能找出一個腫瘤標記，協助醫師於術前正確診斷出甲狀腺癌，是非常重要的。
利用反轉錄脢聚合脢鏈反應(reverse transcriptase-polymerase chain reaction, RT-PCR) 這項分子生物學技術，可以偵測極少量的mRNA，它的作法是先萃取RNA之後，再利用反轉錄脢製造 complementary DNA (cDNA)，隨後以cDNA進行聚合脢鏈反應(PCR)反應，將所要檢查的基因放大來研究。我們感到興趣的基因有兩個:一個是鈉碘共同轉運器(sodium iodide symporter, 簡稱NIS)，另一個是端粒脢反轉錄脢(human telomerase reverse transcriptase，簡稱hTERT)。
自從Dr Dai 在1996 cloned and sequenced rNIS，關於hNIS的研究有如雨後春筍般展開，人類的鈉碘共運器(hNIS)是一個內生性膜蛋白，它由15個存在於膜內外區所組成，結構與其他與鈉相關的運送器類似。一直到目前為止，NIS 在不同的甲狀腺組織或是甲狀腺細胞株的表現量上無定論，本研究採用RT-PCR去偵測不同的甲狀腺組織，包括新鮮正常的甲狀腺和甲狀腺癌組織其NIS mRNA的反應。結果發現3個正常甲狀腺組織其NIS mRNA全部是陽性反應，8個結節性甲狀腺腫組織中有6個陽性反應，而2個甲狀腺機能亢進，3個濾泡性腺瘤中的1個，和10個乳突癌中的5個組織，1個濾泡癌也都是陽性反應，但是1個轉移性甲狀腺癌組織是陰性反應。由上述結果顯示NIS mRNA 在正常良性、甲狀腺機能亢進、和結節性甲狀腺腫的組織有比較高比率的陽性反應 (84.6%)，然而，濾泡性腺瘤、乳突癌和濾泡癌，其反轉錄脢聚合反應的結果陽性率偏低 (46.7%)。hNIS在體外和體內反應的不同，值得進一步去探討。結論: hNIS在正常和良性的甲狀腺組織的表現量高於其在惡性甲狀腺組織的表現量，除此之外，對大部分甲狀腺乳突癌組織而言，利用反轉錄脢聚合反應方法無法測得其hNIS的存在。hNIS目前的研究方向，主要是朝131I癌症掃描以及131I的治療-在甲狀腺癌及非甲狀腺癌(如乳癌，攝護腺，glioma等)。
最近的研究發現偵測甲狀腺抽吸細胞內人類的端粒脢反轉錄脢的基因表現，可以當作一個診斷甲狀腺腫瘤的標記。在這個研究中，我們在手術前由27個”疑是”甲狀腺癌所取得的甲狀腺抽吸細胞，藉由RT-PCR檢驗hTERT mRNA 的表現，細胞和病理學的檢驗結果也同時拿來比較。結果顯示14個甲狀腺癌中，有13個(92.8%)細針穿刺的檢體是陽性反應(包括8個甲狀腺乳突癌、3個濾泡癌和2個何式細胞癌)。相反的，13個良性的甲狀腺瘤的細針穿刺的檢體中，有8個(61.5%)是陽性反應(包括3個甲狀腺結節、2個葛瑞芙氏症、1個何式細胞瘤和1個濾泡性腺瘤)，hTERT mRNA在甲狀腺惡性腫瘤比在良性腫瘤有比較高的陽性率。良性和惡性濾泡型甲狀腺腫瘤中hTERT表現量的差異值得進一部探討。我們需要更多的資訊，諸如半定量的即時反轉錄脢聚合脢鏈反應(real-time RT-PCR)來確認它的臨床應用是否可以作為甲狀腺癌手術前診斷的的一個輔助性的分生標記。

Thyroid cancer is the eighth leading cancer among female Taiwanese. Although many scientists have done a lot of researches to investigate this disease, the tumorigenesis of thyroid tumors remains unclear. Fine-needle aspiration (FNA) had been widely established as the key diagnostic tool for preoperative selection of nodules at risk of malignancy. However, preoperative diagnosis of thyroid cancer, especially for those diagnosed as follicular neoplasm (up to 30% in all thyroid tumors) is challenging most physicians. To verify a reliable tumor marker, which can help to distinguish between benign and malignant thyroid tumors, therefore is very important. Reverse transcription-polymerase chain reaction (RT-PCR) is a very sensitive technique which allow us to detect very low levels of mRNA. This technique involves the isolation of RNA to generate , by reverse transcription, complementary DNA (cDNA), which is then used as a template for PCR to amplify selected regions of targeted genes. Our major interesting genes here are human sodium iodide symporter (hNIS) and human telomerase reverse transcriptase (hTERT).
Since the rNIS was cloned and sequenced in 1996 (Dai), a lots of researches of this protein has been done. Human sodium iodide symporter (hNIS) is an intrinsic membrane protein with 12 transmembrane regions, which shows homology to other sodium-dependent transporters. There is controversy as to the amount of hNIS expression in different kinds of human thyroid cancer tissues and cell lines. In our study, RT-PCR was used to detect mRNA of hNIS in various fresh normal, benign tissues and malignant human thyroid tissues. The results revealed three of three normal tissues, six of eight nodular hyperplasia, two of two hyperthyroidism, one of three follicular adenomas, five of ten papillary carcinomas, one of one follicular carcinoma and zero of one metastatic follicular tissues demonstrated positive results for hNIS in thyroid epithelial cells. A higher percentage of positive results of the symporter mRNA were found in normal benign thyroid tissues and the thyroid tissues of hyperthyroidism, and nodular hyperplasia (84.6%); however follicular adenoma, papillary and follicular thyroid carcinomas demonstrated a lower percentage of expression in the RT-PCR studies (46.7%). The discrepancies of the expression of hNIS in in vivo and in vitro studies need further investigation. In conclusion, hNIS was found in higher ratios in normal and benign thyroid tissues than in the malignant tissues. In addition, the RT-PCR technique hNIS did not detect the transporter in most papillary thyroid cancer tissues. The major application of research in hNIS is for cancer work-up and 131Itreatment of thyroid and extrathyroid malignancies.
Recently, the detection of human telomerase reverse transcriptase (hTERT) gene expression in thyroid FNA samples has been found to be a promising diagnostic marker in the distinction of benign from malignant thyroid tumors. In our next study, we prospectively collected 27 presurgical FNA samples from thyroid tumors that were suspicious for malignancy. hTERT gene expression was examined by RT-PCR. Cytological and histological results were also compared. The results demonstrated that 13 (92.8%) of 14 thyroid carcinomas, including 8 of 8 papillary and 2 Hürthle cell thyroid carcinomas have corresponding FNA samples that were positive for hTERT. In contrast, 8 (61.5%) of 13 benign thyroid nodules, including 3 of 6 nodular goiter, 2 of 2 Graves’ disease, 2 of 2 Hürthle cell adenomas, and 1 of 3 follicular adenomas were positive for hTERT. The degree of differences in hTERT expression between benign and malignant follicular thyroid tumors needs further investigation. We need more information such as semi-quantitative real-time RT-PCR to verify that whether its application could serve as an adjunctive molecular marker for preoperative diagnosis of thyroid malignancies.

目錄 頁數
指導教授授權書
口試委員會審定書
授權書
致謝
目錄
圖表目錄
縮寫對照表
中文總摘要
英文總摘要
1.綜論
1-1甲狀腺癌的流行病學
1-2甲狀腺癌的致病基轉
1-3 甲狀腺癌術前的診斷
1-4 端粒脢 (Telomerase) 與甲狀腺癌
1-5 鈉碘共同轉運器 (Sodium iodide symporter，簡稱NIS)
1-6 研究新的癌症標記
2.第一部份: 不同甲狀腺疾病組織sodium iodide sympoter之表現
2-1 中文摘要
2-2 英文摘要
2-3 引言
2-4 病人及方法
2-4-1 病人之篩選和組織的取得
2-4-2人類甲狀腺癌細胞株
2-4-3 實驗方法
2-5 結果
2-6 討論
3.第二部分: 不同甲狀腺疾病細針抽取物hTERT 之mRNA之表現
3-1 中文摘要
3-2 英文摘要
3-3 引言
3-4 病人及方法
3-4-1 病人之篩選
3-4-2 實驗方法
3-5 結果
3-6 討論
4.參考文獻
5.著作附件 (共二篇)
圖表目錄
圖 1.1980-1991年,林口長庚醫院甲狀腺癌病例之統計
圖 2. 甲狀腺癌形成的基轉
圖 3. hNIS 的解剖位置圖(a)和基因結構(b)
圖 4,5. 用cDNA microarray 來比較濾泡性甲狀腺瘤和濾泡性甲狀腺
癌細胞株
圖 6. 不同甲狀腺組織RT-PCR的結果,使用一對hNIS 探針放大的
產物大小是278 bp
圖 7. 27位甲狀腺濾泡腫瘤病人細針穿刺檢體中RT-PCR 放大的
hTERT的表現
表1 .甲狀腺腫瘤的分類 (WHO)
表 2. 家族性甲狀腺癌
表 3. 針對細針穿刺檢體,以RT-PCR 和免疫組織染色法偵測可能
的甲狀腺癌標記
表 4. 不同甲狀腺組織RT-PCR的結果
表 5. 分化良好甲狀腺癌病人的臨床特徵和RT-PCR的結果
表 6. 27位甲狀腺濾泡腫瘤病人的基本特性與細針穿刺檢體中
hTERT的表現
縮寫對照表
AC anaplastic cancer
cDNA complementary DNA
CA 19-9 carcinoma antigen 19-9
CD-15 antibody against a sugar epitope also included Lewis X
blood group antigen
dNTPs deoxyribonucleoside triphosphates
FC follicular cancer
FN follicular neoplasm
FNA fine needle aspiration
EGF epidermal growth factor
HBME-1 monoclonal antibody against the microvillous surface
of mesothelial cells
HMFG antitumour murine monoclonal antibody
hNIS human sodium iodide symporter
hTERT human telomerase reverse transcriptase
MEN multiple endocrine neoplasia
MTC medullary thyroid cancer
MUC1 mucin protein
PC papillary cancer
PPAR peroxisome proliferator activated receptor
PTC papillary thyroid cancer
RT-PCR reverse transcriptase-polymerase chain reaction
Tg thyroglobulin
TSH thyrotropin

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